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Defining the phenotype and diagnostic considerations in adults with congenital disorders of N-linked glycosylation Expert Rev. Mol. Diagn. 14(2), 217–224 (2014)
David FGJ Wolthuis1,2, Miriam C Janssen2, David Cassiman3, Dirk J Lefeber2, Eva Morava-Kozicz*1 1 Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, 70112, USA 2 Radboud University Medical Center Nijmegen, Nijmegen, Netherlands 3 University of Leuven, Leuven, Belgium *Author for correspondence: [email protected]
Congenital disorders of N-glycosylation (CDG) form a rapidly growing group of more than 20 inborn errors of metabolism. Most patients are identified at the pediatric age with multisystem disease. There is no systematic review on the long-term outcome and clinical presentation in adult patients. Here, we review the adult phenotype in 78 CDG patients diagnosed with 18 different forms of N-glycosylation defects. Characteristics include intellectual disability, speech disorder and abnormal gait. After puberty, symptoms might remain non-progressive and patients may lead a socially functional life. Thrombosis and progressive symptoms, such as peripheral neuropathy, scoliosis and visual demise are specifically common in PMM2-CDG. Especially in adult patients, diagnostic glycosylation screening can be mildly abnormal or near-normal, hampering diagnosis. Features of adult CDG patients significantly differ from the pediatric phenotype. Non-syndromal intellectual disability, or congenital malformations in different types of CDG and decreasing sensitivity of screening might be responsible for the CDG cases remaining undiagnosed until adulthood. KEYWORDS: adult metabolic disease • ataxia • cataract • CDG • N-linked glycosylation • scoliosis • thrombosis
Glycosylation is a complex metabolic pathway that starts with the activation of sugar residues in the cytoplasm, followed by building and processing of glycans in the endoplasmic reticulum (ER) and the Golgi apparatus. In N-linked glycosylation, first a lipid-linked oligosaccharide is built in the ER and then the glycan is covalently bound to an amino group of an asparagine residue of the protein by the oligosaccharyl-transferase enzyme complex [1]. The remodeling of the sugar chains starts already in the lumen of the ER and continues through several additional steps in the Golgi apparatus [2]. Compared to N-glycosylation, protein O-linked glycosylation is mainly restricted to the Golgi, where O-glycans are bound to the serine and threonine hydroxyl groups of proteins. Congenital disorders of N-glycosylation (CDG) form a heterogeneous group of diseases due to abnormal glycosylation processes. On informahealthcare.com
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the basis of recent nomenclature, four different groups can be discriminated: N-linked glycosylation; O-linked glycosylation; lipid-linked and GPI-anchor-linked glycosylation; and multiple pathways and other types [3]. The first CDG patient was described in 1980 [4]. Since then, almost 70 different CDG syndromes have been recognized and the number is still increasing [5]. Most of these disorders have been discovered and studied in infants and children. Since the discovery of the first type, many patients with CDG have reached adulthood. In addition, the number of patients diagnosed with CDG in adulthood is increasing. However, little is documented on the specific recognizable features, disease progression and prognosis for the adult population. Here, we review the phenotype of adult patients reported with CDG involving N-linked glycosylation (TABLE 1). The most common adult types are PMM2-CDG,
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Table 1. N-linked glycosylation defects in adults with the age appropriate phenotypes (unique features in bold). Type
Symptoms described in adults
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N-linked pathway ALG1-CDG (CDG-Ik) MIM 608540
Facial dysmorphism, microcephaly, hypotonia, seizures, strabismus, visual loss, intellectual disability and abnormal hemostasis (relatively milder phenotype)
ALG3-CDG (CDG-Id) MIM 601110
Facial dysmorphism, severe psychomotor disability, cortical visual impairment, microcephaly, cerebral atrophy, hypotonia, gastrointestinal problems, osteopenia (relatively mild phenotype)
ALG6-CDG (CDG-Ic) MIM 603147
Coagulation and endocrine abnormalities, phalangeal hypoplasia, intellectual disability and mild-to-moderate neurologic involvement with ataxia, dysmetria, intention tremor
RFT1-CDG (CDG-In) MIM 612015
Mild dysmorphism, short stature, kyphoscoliosis, intellectual disability, hearing loss, controllable epilepsy, hypotonia, ataxia, spasticity, mild hepatosplenomegaly, coagulopathy, normal visual acuity
DPAGT1-CDG (CDG-Ij) MIM 608093
Myopathy, myasthenia, hypotonia, proximal muscle weakness, muscle cramps, dysarthria, scoliosis, cataract
MAGT1-CDG MIM 300716
Intellectual disability (primarily adults reported)
TUSC3-CDG MIM 611093
Intellectual disability (primarily adults reported)
MGAT2-CDG (CDG-IIa) MIM 212066
Facial dysmorphism, muscle wasting, severe epilepsy, kyphoscoliosis, coagulopathy, psychomotor retardation, osteoporosis, died at 18 years
Multiple pathways PMM2-CDG (CDG-Ia) MIM 212065
Intellectual disability, ataxia, dysarthria, retinitis pigmentosa, peripheral neuropathy, kyphoscoliosis, endocrinopathies, cerebellar hypoplasia, facial dysmorphisms, psychomotor retardation
MPI-CDG (CDG-Ib) MIM 602579
Liver fibrosis, protein-losing enteropathy (less severe)
SRD5A3-CDG (CDG-Iq) MIM 612379
Severe intellectual disability, cataract, coloboma, contractures, facial dysmorphisms, microcephaly, short stature, no brain malformations, in one case no detectable N-glycosylation defect
DPM3-CDG (CDG-Io) MIM 612937
Mild mental retardation and muscle weakness, dilated cardiomyopathy, stroke-like episodes
COG5-CDG (CDG-IIi) MIM 613612
Severe mental retardation, autistic behavior, urinary incontinence
ATP6V0A2-CDG MIM 219200
Dry skin, wrinkled skin, epilepsy, gradual improvement of dysmorphic features and skin symptoms with an almost normalization of the sagging skin to adulthood, normal intellect
TMEM165-CDG (CDG-IIk) MIM 614727
Dwarfism, psychomotor retardation, muscular weakness, fat excess, joint laxity, hepatosplenomegaly, white matter abnormalities, hypoplastic pituitary, osteoporosis and skeletal dysplasia
MAN1B1-CDG MIM 614202
Craniofacial dysmorphism, intellectual disability, obesity
PGM1-CDG 612934
Cardiomyopathy associated with coagulation abnormalities and endocrine disturbance, Pierre Robin sequence, cleft palate
SLC35A1-CDG (CDG-IIf) MIM 603585
Bleeding tendency, intellectual disability, epilepsy, renal failure
CDG: Congenital disorders of N-glycosylation.
DPAGT1-CDG and MAN1B1-CDG. More than 30 patients have been described surviving to adulthood with PMM2-CDG [6], and the reported number of adult patients is getting close to 20 with DPAGT1-CDG [7] and MAN1B1-CDG [8]. Here, we review reported adult patients (>18 years of age) with 18 different biochemical CDG subtypes. 218
Diagnostics in adult patients
For diagnostic CDG screening, analysis of serum transferrin N-glycosylation is widely used, most commonly by isofocusing, HPLC [9] or capillary zone electrophoresis [10]. Mass spectrometry of immunopurified transferrin from serum allows more sensitive detection of CDG-I abnormalities [11]. There are basically Expert Rev. Mol. Diagn. 14(2), (2014)
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Diagnostic considerations in CDG
two different patterns that can be identified: type 1 pattern (CDG-I), which is characterized by increased amounts of asialoand disialo-transferrin, and type 2 pattern (CDG-II), which appears with increased asialo-, monosialo-, disialo- and trisialotransferrin bands of variable intensity [12]. Some forms of CDG with abnormal N-glycosylation, such as GCS1-CDG and SLC35C1-CDG, will be missed in routine CDG screening since the defect will not influence the presence of negatively charged sialic acid residues [13,14]. The diagnostic process for CDG-I can be complicated in adults, because mildly abnormal to nearnormal transferrin profiles are common in adolescents and adults with CDG [6]. In the era of next generation sequencing we have discovered several new CDG forms. This ingenious test also helped to identify adult patients with already known forms of N-linked glycosylation disorders, who we would have missed by traditional screening methods [8,15]. The hypothesis behind this is that improving glycosylation is due to a decreasing metabolic flux through the glycosylation pathway in adults. In several occasions, patients with enzymatically and genetically confirmed PMM2-CDG and DPGAT1-CDG and in STT3B-CDG routine CDG screening showed (near)-normal profiles in adolescents [16]. In such cases, a more sensitive analysis by mass spectrometry allowed the identification of glycan loss as a characteristic of CDG-I defects [6,17]. Additionally, normal transferrin analysis has been reported in SRD5A3-CDG in an adult patient with atypical presentation [15]. Also, in X-linked mental retardation due to MAGT1 or in TUSC3 mutations, due to defective oligosaccharyl transferase function, routine CDG screening can be normal [12,18,19]. It is important to note that most of the adolescent and adult CDG-I patients present with abnormal screening results. For CDG-II diagnostics, the recently described UDP-galactose transporter defect SLC35A2-CDG was reported to show a normalization of the previously abnormal glycosylation profile, due to skewed X-inactivation or mosaicism [20]. Few juvenile/adult patients with genetically confirmed CDG-II defect have been reported, but SLC35A1-CDG [21], MGAT2-CDG [22] and B4GALT1-CDG [23] all present with clearly abnormal CDG screening [13]. NGS techniques will provide new opportunities to unravel the genetic causes for glycosylation disorders, such as the CDG-II trafficking defects, but also the many glycosylation defects that cannot be identified via transferrin screening [12]. In the clinical practice, in case of a strong suspicion of CDG, especially in adults, mass spectrometry or NGS might be needed to discover patients, even with known forms of CDG. Clinical features N-linked glycosylation pathway-related defects
The number of adults published with an N-linked glycosylation disorder has exceeded 30. While the reported number of ALG1-CDG patients is increasing, only one adult aged 21 has been described. ALG1-CDG shows a severe, frequently lethal neurological phenotype in children with seizures and visual informahealthcare.com
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loss. A milder course has been observed with intellectual disability and abnormal hemostasis in adults, suggesting that milder defects might be compatible with survival reaching adulthood [24]. An adult patient with ALG3-CDG was described at the age of 21 years. This male patient had a relatively mild phenotype during childhood including feeding difficulties, seizures, cerebral atrophy, gastrointestinal problems and lack of spontaneous pubertal changes. He had intellectual disability and never developed verbal skills. Eye abnormalities included cortical visual impairment, divergent strabismus, horizontal nystagmus and mild optic atrophy [25]. Only a few adults are known with the relatively common CDG type – ALG6-CDG. A female patient at 21 years of age has been reported with ALG6-CDG who had brachydactyly, deep-vein thrombosis, pseudotumor cerebri with normal brain MRI and endocrine abnormalities including hyperandrogenism with virilization [26]. This phenotype drew attention to the presence of limb abnormalities in ALG6-CDG, including distal limb reduction, which could be misleading in the differential diagnosis [27]. Adults with RFT1-CDG show a milder phenotype than children. Reported patients at age 19 and 21 years had controllable epilepsy, coagulopathy without clinical consequences and absence of visual impairment and only one patient was reported with deafness. However, these adult RFT1-CDG patients demonstrated profound intellectual disability [28]. DPAGT1-CDG is an exciting example of CDG imitating other disorders. Myasthenia gravis has been the diagnosis in several adult patients for many years, only discovering the underlying congenital glycosylation defect in adult age ranging from 25 to 57 years [7,29]. Myasthenia occurs due to abnormal glycosylation of the acetylcholine receptor in DPAGT1-CDG and has been reported as presenting symptom of ALG2- and ALG14-CDG as well. DPAGT1-CDG has also been described in two adult patients, diagnosed at around the age of 30 years, with mental retardation [17]. Why abnormal glycosylation affects the neuromuscular junction in this specific type of CDG much more frequently than in other biochemically comparable defects is not yet well understood. Another feature, which is in some cases already present in childhood, but mostly present in adulthood, is cataract [30]. Non-syndromic mental retardation in MAGT1-CDG and TUSC3-CDG has been described mostly in adults, and generally without additional features [19,31]. Only one patient with MGAT2-CDG was ever described to survive to adulthood. Interestingly, this patient had several dysmorphic features, psychomotor retardation, kypho-scoliosis, hormonal abnormalities, coagulopathy and bleeding tendency, muscle wasting and severe epilepsy, which led to his death at 18 years [32]. Multiple pathway-related defects
The number of adults published with the involvement of multiple glycosylation pathway involvement has been approaching 50. Previously listed as isolated N-linked glycosylation defect, 219
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PMM2-CDG (formerly CDG-Ia) is the most important form of this group affecting multiple glycosylation pathways (N-linked glycolysation and GPI-anchor synthesis) [33]. Organ involvement and outcome in adult CDG patients is studied most extensively in this form. More than 30 PMM2-CDG adults have been reported. Some of the PMM2-CDG patients are already in their 40s and show a relatively milder phenotype than expected based on early lethality of severe PMM2-deficient patients in childhood. Most surviving patients show nonprogressive symptoms, including mild-to-severe mental retardation, ataxia, dysarthria, retinitis pigmentosa, cataract SUPPLEMENTARY FIGURE 1 (supplementary material can be found online at www. informahealthcare.com/suppl/10.1586/14737159.2014.890052) and variable degree of peripheral neuropathy. Kyphoscoliosis, osteoporosis and endocrinopathies (hypothyroidism, hypogonadotropic hypogonadism) are frequent symptoms in adults with PMM2-CDG [34,35]. Adults with PMM2-CDG have been previously observed as incidental diagnosis in siblings of affected patients, but several cases are known with mild neurologic symptoms, or intellectual disability, as the only manifestation of the disease [36]. Absent speech can be a huge barrier in communication in adult life in reaching independence, but patients can frequently communicate by a communication device. Retinitis pigmentosa is unfortunately very common in adult PMM2-CDG, having a major impact on life quality [34]. Low levels of glycosylated coagulation factors are typically observed in childhood, but normalization of factor IX and XI activity might occur during maturation, parallel with the improvement of transferrin isoform abnormalities (personal observation) [6]. Unfortunately, thrombosis remains a common, life-threatening complication in adults with this particular type of CDG [37]. Although hypogonadism is typical for PMM2-CDG, patients with normal puberty and menstruation have also been described [38]. Some of the late diagnosed cases have only mild transferrin abnormalities and stress-related titubation, but normal intelligence [6]. Hyperinsulinism, if persisting to adulthood, is difficult to treat, but fortunately rare [34]. Adults with MPI-CDG (formerly CDG-Ib) frequently have a less prominent protein-losing enteropathy and hypoalbuminemia compared to that in childhood [39]. The most striking symptom at a later age is the progression of the liver fibrosis, leading to hepatic insufficiency and cirrhosis. The thrombosis risk is still high, especially during stress and invasive surgery, but spontaneous bleeding episodes, even on mannose therapy and relatively normal coagulation parameters, might occur. Recently, the first liver transplantation was performed in a patient with MPICDG [40]. It is interesting to note that completely symptom-free individuals have been also observed as an accidental finding [41]. Adult patients with SRD5A3-CDG have been described with severe intellectual disability, variable degree of vermis hypoplasia, kyphosis, coloboma and cataract (SUPPLEMENTARY FIGURE 1). The phenotype is highly different from the multisystem involvement in children with the same disease [42,43]. Interestingly, this later defect of the lipid-linked glycosylation pathway 220
had no detectable N-linked glycan abnormalities in adulthood by transferrin analysis [15]. An adolescent DOLK-CDG patient was described with isolated dilated cardiomyopathy [44]. This particular patient who was diagnosed during puberty did not survive into adulthood because of delay in heart transplantation and died at the age of 16.5 years. Some of the younger children had transient developmental delay, while there was also a strong presence of cardiac disease in pediatric patients. In most of the cases, cardiac transplantation became necessary due to the progressive cardiac insufficiency [44]. DPM-CDG is a growing group of N-linked glycosylation disorders associated with alpha-dystroglycanopathy [45]. A 27-yearold female patient was reported with DPM3-CDG with low normal IQ and mild muscle weakness. She presented initially at 11 years with mild type 1 isofocusing profile and mild muscle weakness and waddling gait. She was found to have dilated cardiomyopathy without signs of cardiac muscle hypertrophy at age 20 years followed by a stroke-like episode at 21 years [46]. DPM2- and DPM1-CDG have thus far only been described in children with muscle dystrophy and severe epilepsy [45]. COG complex-related CDGs are usually severe and rarely survive to adulthood. These patients have a combined N- and O-linked glycosylation defect, similar to that seen in ATP6V0A2-CDG due to a global Golgi trafficking defect [47]. Interestingly, two adult patients with COG5-CDG have been described at 19 and 28 years. These siblings had developmental delay, hypotonia, microcephaly and intellectual disability. Urine incontinence was present in both cases, and they were mostly dependent on their environment for daily activities [48]. Patients diagnosed with ATP6V0A2-CDG show a classic clinical presentation of autosomal recessive cutis laxa type II after birth, biochemical abnormalities of N- and O-linked glycosylation and mild liver and coagulation involvement [49]. Although they have a multisystem disease associated with severe skin wrinkling, intriguingly they show a gradual improvement of the skin symptoms (SUPPLEMENTARY FIGURE 1), leading to minimal sagging skin to adulthood [50]. There is variable intellectual disability, in some cases normal IQ, but the seizure disorder might persist. One adult patient has no other features, but seizures and an ATP6V0A2 defect [51]. Dwarfism was the most striking feature in a reported adult patient of 19 years with TMEM165-CDG. Additional to skeletal dysplasia, other features included excess of fat, eye abnormalities, osteoporosis, joint laxity, psychomotor retardation, hypoplastic pituitary and white mater abnormalities [52]. Unsolved cases of CDG type I and II, commonly referred to as CDG Ix and IIx respectively, have also been described to reach adulthood. Interestingly, CDG IIx may present with a chronic mild elevation of serum transaminases, even in adults [53]. New CDG forms
Under this section, we included three recently defined CDG forms, where several adult patients have been described. MAN1B1 defect has been originally discovered as a disorder with intellectual disability [8], and just recently confirmed to be Expert Rev. Mol. Diagn. 14(2), (2014)
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a form of CDG with developmental delay, behavioral and learning problems and craniofacial dysmorphic features. It has been included in the disorders of N-linked glycosylation, although initially no secretory glycosylation alterations were shown in the patients [8]. The enzyme defect leads to abnormal quality control of glycoproteins and a CDG type II glycosylation pattern [54]. Excitingly, this type of intellectual disability, therefore, is screenable by transferrin assays. Truncal obesity, inverted nipples, wrinkled skin and liver involvement have been described in pediatric and adult cases, but seizures have only been found in pediatric patients [8,54,55]. An even more intriguing type of an inborn error associated with glycosylation defects seems to show two different clinical presentations when presenting in adults, or primarily in children. The original report on a PGM1 defect in adulthood was comparable to the clinical phenotype of a glycogenosis disease: patients showing exercise intolerance, fatigue and muscle pain [56] However, since then, several pediatric patients have been observed with congenital midline malformations of the palate, recurrent hypoglycemia and endocrine, liver and cardiac diseases, but without significant muscle disease or rhabdomyolysis [57]. In this newly redefined inborn error, PGM1-CDG, two adult patients with exercise intolerance remained stable, and two pediatric patients reached adulthood and developed cardiomyopathy associated with growth delay, coagulation abnormalities and endocrine disturbance, associated with a unique abnormal, mixed glycosylation pattern (CDG-I/CDG-II) [58]. Another new CDG form was rediscovered as a secretory glycosylation disorder in an adult. SLC35A1-CDG was originally described as a disorder with thrombocytopenia without secretory glycan abnormalities. This sialic acid transport disorder has been recently redefined as multisystem disease with a type II CDG pattern. The patient was diagnosed with SLC35A1-CDG only in adulthood. Psychomotor delay and tonic-clonic seizures started in childhood, and at the age of 20 the patient was first evaluated for dysmorphic features and neurological symptoms. Macrothrombocytopenia, proteinuria, aminoaciduria and decreased free thyroxine and estradiol levels were found. Reduced levels of different coagulation factors resolved spontaneously. However, bleeding complications after endoscopic cholangio-pancreaticography led to her premature death at the age of 22 years [21]. Prognosis & therapy in adult CDG
In general, we do see a higher rate of long-term survival in patients with a neurologic phenotype in CDG [6,59,60]. Interestingly, most of the reported adult CDG cases are not follow-up patients, but patients discovered at an adult age. The mutation spectrum, however, is not significantly different from the mutations detected in the same disorder when the diagnosis was found in children, especially in PMM2-CDG [6,60]. Based on the experience of long-term survival, in some PMM2-CDG patients even with an infantile multisystem phenotype, severe mutations and a classic glycosylation defect, we have to conclude that the severity of the biochemical abnormality at the informahealthcare.com
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time of diagnosis does not always predict the diagnosis, and supportive therapy, good nutrition, early use of antibiotics, avoidance of elective surgeries and physiotherapy are the major determining factors of outcome [6,60,61]. There are only a few subtypes of CDG with a specific treatment option in adults. MPI-CDG is the type that has been treated most successfully with the supplementation of mannose [62]. The metabolic defect is in the phosphomannose isomerase (PMI), which converts fructose-6-phosphate into mannose6-phosphate, a precursor of GDP-mannose, which is necessary for proper glycosylation. Through administration of mannose, this defect is elegantly bypassed and leads to a glycosylation pattern, which is almost completely normalized. Clinical symptoms greatly improve [63] as well, especially coagulation abnormalities and protein-losing enteropathy, bridging the defect and using hexokinase to deliver mannose to the glycosylation pathway [64]. Therapy seems to be more efficient in children than in adults, and adults might deliver some resistance to mannose supplementation (personal observation). Some of the clinical manifestations of PMI-deficiency, however, spontaneously improve with age, even without mannose therapy, especially the chronic diarrhea. It is hypothesized that this is due to up-regulation of the mannose transporter and increased activity of phosphoglucose isomerase, which has been described to catalyze the same reaction as the PMI enzyme [39,65]. Interestingly, in mannose-resistant cases, intravenous heparin therapy was found to be useful to treat the abnormal mucosal glycosylation in the bowels and improving symptoms in protein-losing enteropathy in adults [66]. A similar positive outcome has been reported in two young adults with PGM1-deficiency, who showed a mixed type I/type II pattern and decreased galactosylation by mass spectrometry. The patients experienced significant advancement of biochemical parameters and improvement of clinical features on galactose supplementation [57]. An interesting aspect of therapy in CDG is the use of acetylcholin-reuptake inhibitors in patients with DPAGT1-CDG. Although this is symptomatic treatment, and does not resolve the underlying metabolic defect, there is a significant improvement of the myasthenic features in children with DPAGT1-CDG. Unfortunately, these effects seem to diminish during the aging of the patients [29]. With respect to other CDG types, symptomatic treatment remains the treatment of choice in patients until more targeted treatments come available. One should emphasize, however, the specific need for treating osteoporosis and neuropathic pain in adults with CDG, especially in adult PMM2-CDG. Discussion
Unfortunately 25% of patients with CDG die in the first few years of life. The ones that survive were often diagnosed in childhood and are currently growing into adults, but also the ones diagnosed in adulthood frequently show a different phenotype. Examples include scoliosis, neuropathy and retina abnormalities in adult PMM2-CDG, myasthenia without CNS involvement in DPAGT1-CDG, liver cirrhosis in MPI-CDG, 221
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primary muscle presentation on PGM1-CDG and so on, (for specific features see bold features in TABLE 1) [7,40,57,60]. Once the patient reaches adulthood, CDG can be non-progressive, but patients rarely reach independence [39,67]. The wide variety of clinical presentation and disease severity in adults is the best described common CDG form – PMM2-CDG (SUPPLEMENTARY FIGURE 1). The phenotypic spectrum of PMM2-CDG keeps expanding, particularly at the less severe end where even patients with a normal cognitive function have been described [36]. Interestingly, diagnosis in this form can also be delayed to adult age [67]. Although adult patients with CDG hardly ever are symptom-free in childhood, the symptoms of DPAGT1-CDG, however, may begin only in adulthood [7]. Importantly, when CDG manifests as isolated symptoms and malformations, like a congenital cardiac malformation, or speech delay and intellectual disability, instead of a systemic disease, a late diagnosis is more likely. Concluding, the features of adult CDG patients may differ from the classical phenotype, as it is described in children. We propose to include CDG in the differential diagnosis in adults with unexplained neurologic symptoms and non-progressive intellectual disability, especially in association with hormonal or hemostatic abnormalities. Additional to the classic syndromal presentation with cerebellar vermis ataxia, facial dysmorphism and abnormal fat distribution, diverse congenital malformations are present in different types of CDG. The presence of unique malformations like congenital heart disease (Tetralogy of Fallot or VSD), eye malformations, like coloboma, distal limb reduction, skeletal dysplasia or palatoschisis in others might be responsible for the fact that several cases with CDG remain
undiagnosed to adulthood. The absence of neurologic disease in some CDG patients or mild learning disorder makes the diagnosis also difficult. For diagnostic testing, routine CDG screening could be applied as a first step, knowing that the TIEF may fail. However, if normal, more sensitive methods like mass spectrometry could be applied or direct testing of enzymes or genes. Expert commentary & five-year view
Glycosylation is a dynamic metabolic process, which is present in all cell compartments and essential in almost all functional aspects of the human body. It plays a role in organ development to metabolism; brain function; transport; signaling and immune, endocrine and stress response. The number of adults reported with N-linked glycosylation is close to a hundred, diagnosed with 18 different forms of N-glycosylation defects, mostly presenting with intellectual disability and neurologic symptoms. CDG forms a heterogeneous group. There are almost 100 distinct metabolic defects affecting glycosylation. New disorders are discovered almost monthly, making glycosylation one of the most common metabolic pathways involved in syndromal inborn errors of metabolism. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Most patients with congenital disorders of N-glycosylation (CDG) with abnormal N-glycosylation are diagnosed in the pediatric age and a multisystem presentation. • N-linked CDG leads to early death in about 25% of the patients. • Most children with CDG without multisystem involvement reach adulthood. • The common adult phenotype involves intellectual disability, speech disorder, visual loss, neuropathy and ataxia. • Systemic involvement in adult includes scoliosis, cataract and episodes of venous thromboses. • New types of CDGs have been defined in adults with isolated neurologic phenotype or intellectual disability. • In adult patients, CDG screening can be near-normal, hampering the diagnosis. • Due to congenital malformations, CDG cases might remain undiagnosed until adulthood.
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Expert Rev. Mol. Diagn. 14(2), (2014)
Review
Defining the phenotype and diagnostic considerations in adults with congenital disorders of N-linked glycosylation Expert Rev. Mol. Diagn. 14(2), 217–224 (2014)
David FGJ Wolthuis1,2, Miriam C Janssen2, David Cassiman3, Dirk J Lefeber2, Eva Morava-Kozicz*1 1 Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, 70112, USA 2 Radboud University Medical Center Nijmegen, Nijmegen, Netherlands 3 University of Leuven, Leuven, Belgium *Author for correspondence: [email protected]
Congenital disorders of N-glycosylation (CDG) form a rapidly growing group of more than 20 inborn errors of metabolism. Most patients are identified at the pediatric age with multisystem disease. There is no systematic review on the long-term outcome and clinical presentation in adult patients. Here, we review the adult phenotype in 78 CDG patients diagnosed with 18 different forms of N-glycosylation defects. Characteristics include intellectual disability, speech disorder and abnormal gait. After puberty, symptoms might remain non-progressive and patients may lead a socially functional life. Thrombosis and progressive symptoms, such as peripheral neuropathy, scoliosis and visual demise are specifically common in PMM2-CDG. Especially in adult patients, diagnostic glycosylation screening can be mildly abnormal or near-normal, hampering diagnosis. Features of adult CDG patients significantly differ from the pediatric phenotype. Non-syndromal intellectual disability, or congenital malformations in different types of CDG and decreasing sensitivity of screening might be responsible for the CDG cases remaining undiagnosed until adulthood. KEYWORDS: adult metabolic disease • ataxia • cataract • CDG • N-linked glycosylation • scoliosis • thrombosis
Glycosylation is a complex metabolic pathway that starts with the activation of sugar residues in the cytoplasm, followed by building and processing of glycans in the endoplasmic reticulum (ER) and the Golgi apparatus. In N-linked glycosylation, first a lipid-linked oligosaccharide is built in the ER and then the glycan is covalently bound to an amino group of an asparagine residue of the protein by the oligosaccharyl-transferase enzyme complex [1]. The remodeling of the sugar chains starts already in the lumen of the ER and continues through several additional steps in the Golgi apparatus [2]. Compared to N-glycosylation, protein O-linked glycosylation is mainly restricted to the Golgi, where O-glycans are bound to the serine and threonine hydroxyl groups of proteins. Congenital disorders of N-glycosylation (CDG) form a heterogeneous group of diseases due to abnormal glycosylation processes. On informahealthcare.com
10.1586/14737159.2014.890052
the basis of recent nomenclature, four different groups can be discriminated: N-linked glycosylation; O-linked glycosylation; lipid-linked and GPI-anchor-linked glycosylation; and multiple pathways and other types [3]. The first CDG patient was described in 1980 [4]. Since then, almost 70 different CDG syndromes have been recognized and the number is still increasing [5]. Most of these disorders have been discovered and studied in infants and children. Since the discovery of the first type, many patients with CDG have reached adulthood. In addition, the number of patients diagnosed with CDG in adulthood is increasing. However, little is documented on the specific recognizable features, disease progression and prognosis for the adult population. Here, we review the phenotype of adult patients reported with CDG involving N-linked glycosylation (TABLE 1). The most common adult types are PMM2-CDG,
Ó 2014 Informa UK Ltd
ISSN 1473-7159
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Table 1. N-linked glycosylation defects in adults with the age appropriate phenotypes (unique features in bold). Type
Symptoms described in adults
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N-linked pathway ALG1-CDG (CDG-Ik) MIM 608540
Facial dysmorphism, microcephaly, hypotonia, seizures, strabismus, visual loss, intellectual disability and abnormal hemostasis (relatively milder phenotype)
ALG3-CDG (CDG-Id) MIM 601110
Facial dysmorphism, severe psychomotor disability, cortical visual impairment, microcephaly, cerebral atrophy, hypotonia, gastrointestinal problems, osteopenia (relatively mild phenotype)
ALG6-CDG (CDG-Ic) MIM 603147
Coagulation and endocrine abnormalities, phalangeal hypoplasia, intellectual disability and mild-to-moderate neurologic involvement with ataxia, dysmetria, intention tremor
RFT1-CDG (CDG-In) MIM 612015
Mild dysmorphism, short stature, kyphoscoliosis, intellectual disability, hearing loss, controllable epilepsy, hypotonia, ataxia, spasticity, mild hepatosplenomegaly, coagulopathy, normal visual acuity
DPAGT1-CDG (CDG-Ij) MIM 608093
Myopathy, myasthenia, hypotonia, proximal muscle weakness, muscle cramps, dysarthria, scoliosis, cataract
MAGT1-CDG MIM 300716
Intellectual disability (primarily adults reported)
TUSC3-CDG MIM 611093
Intellectual disability (primarily adults reported)
MGAT2-CDG (CDG-IIa) MIM 212066
Facial dysmorphism, muscle wasting, severe epilepsy, kyphoscoliosis, coagulopathy, psychomotor retardation, osteoporosis, died at 18 years
Multiple pathways PMM2-CDG (CDG-Ia) MIM 212065
Intellectual disability, ataxia, dysarthria, retinitis pigmentosa, peripheral neuropathy, kyphoscoliosis, endocrinopathies, cerebellar hypoplasia, facial dysmorphisms, psychomotor retardation
MPI-CDG (CDG-Ib) MIM 602579
Liver fibrosis, protein-losing enteropathy (less severe)
SRD5A3-CDG (CDG-Iq) MIM 612379
Severe intellectual disability, cataract, coloboma, contractures, facial dysmorphisms, microcephaly, short stature, no brain malformations, in one case no detectable N-glycosylation defect
DPM3-CDG (CDG-Io) MIM 612937
Mild mental retardation and muscle weakness, dilated cardiomyopathy, stroke-like episodes
COG5-CDG (CDG-IIi) MIM 613612
Severe mental retardation, autistic behavior, urinary incontinence
ATP6V0A2-CDG MIM 219200
Dry skin, wrinkled skin, epilepsy, gradual improvement of dysmorphic features and skin symptoms with an almost normalization of the sagging skin to adulthood, normal intellect
TMEM165-CDG (CDG-IIk) MIM 614727
Dwarfism, psychomotor retardation, muscular weakness, fat excess, joint laxity, hepatosplenomegaly, white matter abnormalities, hypoplastic pituitary, osteoporosis and skeletal dysplasia
MAN1B1-CDG MIM 614202
Craniofacial dysmorphism, intellectual disability, obesity
PGM1-CDG 612934
Cardiomyopathy associated with coagulation abnormalities and endocrine disturbance, Pierre Robin sequence, cleft palate
SLC35A1-CDG (CDG-IIf) MIM 603585
Bleeding tendency, intellectual disability, epilepsy, renal failure
CDG: Congenital disorders of N-glycosylation.
DPAGT1-CDG and MAN1B1-CDG. More than 30 patients have been described surviving to adulthood with PMM2-CDG [6], and the reported number of adult patients is getting close to 20 with DPAGT1-CDG [7] and MAN1B1-CDG [8]. Here, we review reported adult patients (>18 years of age) with 18 different biochemical CDG subtypes. 218
Diagnostics in adult patients
For diagnostic CDG screening, analysis of serum transferrin N-glycosylation is widely used, most commonly by isofocusing, HPLC [9] or capillary zone electrophoresis [10]. Mass spectrometry of immunopurified transferrin from serum allows more sensitive detection of CDG-I abnormalities [11]. There are basically Expert Rev. Mol. Diagn. 14(2), (2014)
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Diagnostic considerations in CDG
two different patterns that can be identified: type 1 pattern (CDG-I), which is characterized by increased amounts of asialoand disialo-transferrin, and type 2 pattern (CDG-II), which appears with increased asialo-, monosialo-, disialo- and trisialotransferrin bands of variable intensity [12]. Some forms of CDG with abnormal N-glycosylation, such as GCS1-CDG and SLC35C1-CDG, will be missed in routine CDG screening since the defect will not influence the presence of negatively charged sialic acid residues [13,14]. The diagnostic process for CDG-I can be complicated in adults, because mildly abnormal to nearnormal transferrin profiles are common in adolescents and adults with CDG [6]. In the era of next generation sequencing we have discovered several new CDG forms. This ingenious test also helped to identify adult patients with already known forms of N-linked glycosylation disorders, who we would have missed by traditional screening methods [8,15]. The hypothesis behind this is that improving glycosylation is due to a decreasing metabolic flux through the glycosylation pathway in adults. In several occasions, patients with enzymatically and genetically confirmed PMM2-CDG and DPGAT1-CDG and in STT3B-CDG routine CDG screening showed (near)-normal profiles in adolescents [16]. In such cases, a more sensitive analysis by mass spectrometry allowed the identification of glycan loss as a characteristic of CDG-I defects [6,17]. Additionally, normal transferrin analysis has been reported in SRD5A3-CDG in an adult patient with atypical presentation [15]. Also, in X-linked mental retardation due to MAGT1 or in TUSC3 mutations, due to defective oligosaccharyl transferase function, routine CDG screening can be normal [12,18,19]. It is important to note that most of the adolescent and adult CDG-I patients present with abnormal screening results. For CDG-II diagnostics, the recently described UDP-galactose transporter defect SLC35A2-CDG was reported to show a normalization of the previously abnormal glycosylation profile, due to skewed X-inactivation or mosaicism [20]. Few juvenile/adult patients with genetically confirmed CDG-II defect have been reported, but SLC35A1-CDG [21], MGAT2-CDG [22] and B4GALT1-CDG [23] all present with clearly abnormal CDG screening [13]. NGS techniques will provide new opportunities to unravel the genetic causes for glycosylation disorders, such as the CDG-II trafficking defects, but also the many glycosylation defects that cannot be identified via transferrin screening [12]. In the clinical practice, in case of a strong suspicion of CDG, especially in adults, mass spectrometry or NGS might be needed to discover patients, even with known forms of CDG. Clinical features N-linked glycosylation pathway-related defects
The number of adults published with an N-linked glycosylation disorder has exceeded 30. While the reported number of ALG1-CDG patients is increasing, only one adult aged 21 has been described. ALG1-CDG shows a severe, frequently lethal neurological phenotype in children with seizures and visual informahealthcare.com
Review
loss. A milder course has been observed with intellectual disability and abnormal hemostasis in adults, suggesting that milder defects might be compatible with survival reaching adulthood [24]. An adult patient with ALG3-CDG was described at the age of 21 years. This male patient had a relatively mild phenotype during childhood including feeding difficulties, seizures, cerebral atrophy, gastrointestinal problems and lack of spontaneous pubertal changes. He had intellectual disability and never developed verbal skills. Eye abnormalities included cortical visual impairment, divergent strabismus, horizontal nystagmus and mild optic atrophy [25]. Only a few adults are known with the relatively common CDG type – ALG6-CDG. A female patient at 21 years of age has been reported with ALG6-CDG who had brachydactyly, deep-vein thrombosis, pseudotumor cerebri with normal brain MRI and endocrine abnormalities including hyperandrogenism with virilization [26]. This phenotype drew attention to the presence of limb abnormalities in ALG6-CDG, including distal limb reduction, which could be misleading in the differential diagnosis [27]. Adults with RFT1-CDG show a milder phenotype than children. Reported patients at age 19 and 21 years had controllable epilepsy, coagulopathy without clinical consequences and absence of visual impairment and only one patient was reported with deafness. However, these adult RFT1-CDG patients demonstrated profound intellectual disability [28]. DPAGT1-CDG is an exciting example of CDG imitating other disorders. Myasthenia gravis has been the diagnosis in several adult patients for many years, only discovering the underlying congenital glycosylation defect in adult age ranging from 25 to 57 years [7,29]. Myasthenia occurs due to abnormal glycosylation of the acetylcholine receptor in DPAGT1-CDG and has been reported as presenting symptom of ALG2- and ALG14-CDG as well. DPAGT1-CDG has also been described in two adult patients, diagnosed at around the age of 30 years, with mental retardation [17]. Why abnormal glycosylation affects the neuromuscular junction in this specific type of CDG much more frequently than in other biochemically comparable defects is not yet well understood. Another feature, which is in some cases already present in childhood, but mostly present in adulthood, is cataract [30]. Non-syndromic mental retardation in MAGT1-CDG and TUSC3-CDG has been described mostly in adults, and generally without additional features [19,31]. Only one patient with MGAT2-CDG was ever described to survive to adulthood. Interestingly, this patient had several dysmorphic features, psychomotor retardation, kypho-scoliosis, hormonal abnormalities, coagulopathy and bleeding tendency, muscle wasting and severe epilepsy, which led to his death at 18 years [32]. Multiple pathway-related defects
The number of adults published with the involvement of multiple glycosylation pathway involvement has been approaching 50. Previously listed as isolated N-linked glycosylation defect, 219
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Review
Wolthuis, Janssen, Cassiman, Lefeber & Morava-Kozicz
PMM2-CDG (formerly CDG-Ia) is the most important form of this group affecting multiple glycosylation pathways (N-linked glycolysation and GPI-anchor synthesis) [33]. Organ involvement and outcome in adult CDG patients is studied most extensively in this form. More than 30 PMM2-CDG adults have been reported. Some of the PMM2-CDG patients are already in their 40s and show a relatively milder phenotype than expected based on early lethality of severe PMM2-deficient patients in childhood. Most surviving patients show nonprogressive symptoms, including mild-to-severe mental retardation, ataxia, dysarthria, retinitis pigmentosa, cataract SUPPLEMENTARY FIGURE 1 (supplementary material can be found online at www. informahealthcare.com/suppl/10.1586/14737159.2014.890052) and variable degree of peripheral neuropathy. Kyphoscoliosis, osteoporosis and endocrinopathies (hypothyroidism, hypogonadotropic hypogonadism) are frequent symptoms in adults with PMM2-CDG [34,35]. Adults with PMM2-CDG have been previously observed as incidental diagnosis in siblings of affected patients, but several cases are known with mild neurologic symptoms, or intellectual disability, as the only manifestation of the disease [36]. Absent speech can be a huge barrier in communication in adult life in reaching independence, but patients can frequently communicate by a communication device. Retinitis pigmentosa is unfortunately very common in adult PMM2-CDG, having a major impact on life quality [34]. Low levels of glycosylated coagulation factors are typically observed in childhood, but normalization of factor IX and XI activity might occur during maturation, parallel with the improvement of transferrin isoform abnormalities (personal observation) [6]. Unfortunately, thrombosis remains a common, life-threatening complication in adults with this particular type of CDG [37]. Although hypogonadism is typical for PMM2-CDG, patients with normal puberty and menstruation have also been described [38]. Some of the late diagnosed cases have only mild transferrin abnormalities and stress-related titubation, but normal intelligence [6]. Hyperinsulinism, if persisting to adulthood, is difficult to treat, but fortunately rare [34]. Adults with MPI-CDG (formerly CDG-Ib) frequently have a less prominent protein-losing enteropathy and hypoalbuminemia compared to that in childhood [39]. The most striking symptom at a later age is the progression of the liver fibrosis, leading to hepatic insufficiency and cirrhosis. The thrombosis risk is still high, especially during stress and invasive surgery, but spontaneous bleeding episodes, even on mannose therapy and relatively normal coagulation parameters, might occur. Recently, the first liver transplantation was performed in a patient with MPICDG [40]. It is interesting to note that completely symptom-free individuals have been also observed as an accidental finding [41]. Adult patients with SRD5A3-CDG have been described with severe intellectual disability, variable degree of vermis hypoplasia, kyphosis, coloboma and cataract (SUPPLEMENTARY FIGURE 1). The phenotype is highly different from the multisystem involvement in children with the same disease [42,43]. Interestingly, this later defect of the lipid-linked glycosylation pathway 220
had no detectable N-linked glycan abnormalities in adulthood by transferrin analysis [15]. An adolescent DOLK-CDG patient was described with isolated dilated cardiomyopathy [44]. This particular patient who was diagnosed during puberty did not survive into adulthood because of delay in heart transplantation and died at the age of 16.5 years. Some of the younger children had transient developmental delay, while there was also a strong presence of cardiac disease in pediatric patients. In most of the cases, cardiac transplantation became necessary due to the progressive cardiac insufficiency [44]. DPM-CDG is a growing group of N-linked glycosylation disorders associated with alpha-dystroglycanopathy [45]. A 27-yearold female patient was reported with DPM3-CDG with low normal IQ and mild muscle weakness. She presented initially at 11 years with mild type 1 isofocusing profile and mild muscle weakness and waddling gait. She was found to have dilated cardiomyopathy without signs of cardiac muscle hypertrophy at age 20 years followed by a stroke-like episode at 21 years [46]. DPM2- and DPM1-CDG have thus far only been described in children with muscle dystrophy and severe epilepsy [45]. COG complex-related CDGs are usually severe and rarely survive to adulthood. These patients have a combined N- and O-linked glycosylation defect, similar to that seen in ATP6V0A2-CDG due to a global Golgi trafficking defect [47]. Interestingly, two adult patients with COG5-CDG have been described at 19 and 28 years. These siblings had developmental delay, hypotonia, microcephaly and intellectual disability. Urine incontinence was present in both cases, and they were mostly dependent on their environment for daily activities [48]. Patients diagnosed with ATP6V0A2-CDG show a classic clinical presentation of autosomal recessive cutis laxa type II after birth, biochemical abnormalities of N- and O-linked glycosylation and mild liver and coagulation involvement [49]. Although they have a multisystem disease associated with severe skin wrinkling, intriguingly they show a gradual improvement of the skin symptoms (SUPPLEMENTARY FIGURE 1), leading to minimal sagging skin to adulthood [50]. There is variable intellectual disability, in some cases normal IQ, but the seizure disorder might persist. One adult patient has no other features, but seizures and an ATP6V0A2 defect [51]. Dwarfism was the most striking feature in a reported adult patient of 19 years with TMEM165-CDG. Additional to skeletal dysplasia, other features included excess of fat, eye abnormalities, osteoporosis, joint laxity, psychomotor retardation, hypoplastic pituitary and white mater abnormalities [52]. Unsolved cases of CDG type I and II, commonly referred to as CDG Ix and IIx respectively, have also been described to reach adulthood. Interestingly, CDG IIx may present with a chronic mild elevation of serum transaminases, even in adults [53]. New CDG forms
Under this section, we included three recently defined CDG forms, where several adult patients have been described. MAN1B1 defect has been originally discovered as a disorder with intellectual disability [8], and just recently confirmed to be Expert Rev. Mol. Diagn. 14(2), (2014)
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Diagnostic considerations in CDG
a form of CDG with developmental delay, behavioral and learning problems and craniofacial dysmorphic features. It has been included in the disorders of N-linked glycosylation, although initially no secretory glycosylation alterations were shown in the patients [8]. The enzyme defect leads to abnormal quality control of glycoproteins and a CDG type II glycosylation pattern [54]. Excitingly, this type of intellectual disability, therefore, is screenable by transferrin assays. Truncal obesity, inverted nipples, wrinkled skin and liver involvement have been described in pediatric and adult cases, but seizures have only been found in pediatric patients [8,54,55]. An even more intriguing type of an inborn error associated with glycosylation defects seems to show two different clinical presentations when presenting in adults, or primarily in children. The original report on a PGM1 defect in adulthood was comparable to the clinical phenotype of a glycogenosis disease: patients showing exercise intolerance, fatigue and muscle pain [56] However, since then, several pediatric patients have been observed with congenital midline malformations of the palate, recurrent hypoglycemia and endocrine, liver and cardiac diseases, but without significant muscle disease or rhabdomyolysis [57]. In this newly redefined inborn error, PGM1-CDG, two adult patients with exercise intolerance remained stable, and two pediatric patients reached adulthood and developed cardiomyopathy associated with growth delay, coagulation abnormalities and endocrine disturbance, associated with a unique abnormal, mixed glycosylation pattern (CDG-I/CDG-II) [58]. Another new CDG form was rediscovered as a secretory glycosylation disorder in an adult. SLC35A1-CDG was originally described as a disorder with thrombocytopenia without secretory glycan abnormalities. This sialic acid transport disorder has been recently redefined as multisystem disease with a type II CDG pattern. The patient was diagnosed with SLC35A1-CDG only in adulthood. Psychomotor delay and tonic-clonic seizures started in childhood, and at the age of 20 the patient was first evaluated for dysmorphic features and neurological symptoms. Macrothrombocytopenia, proteinuria, aminoaciduria and decreased free thyroxine and estradiol levels were found. Reduced levels of different coagulation factors resolved spontaneously. However, bleeding complications after endoscopic cholangio-pancreaticography led to her premature death at the age of 22 years [21]. Prognosis & therapy in adult CDG
In general, we do see a higher rate of long-term survival in patients with a neurologic phenotype in CDG [6,59,60]. Interestingly, most of the reported adult CDG cases are not follow-up patients, but patients discovered at an adult age. The mutation spectrum, however, is not significantly different from the mutations detected in the same disorder when the diagnosis was found in children, especially in PMM2-CDG [6,60]. Based on the experience of long-term survival, in some PMM2-CDG patients even with an infantile multisystem phenotype, severe mutations and a classic glycosylation defect, we have to conclude that the severity of the biochemical abnormality at the informahealthcare.com
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time of diagnosis does not always predict the diagnosis, and supportive therapy, good nutrition, early use of antibiotics, avoidance of elective surgeries and physiotherapy are the major determining factors of outcome [6,60,61]. There are only a few subtypes of CDG with a specific treatment option in adults. MPI-CDG is the type that has been treated most successfully with the supplementation of mannose [62]. The metabolic defect is in the phosphomannose isomerase (PMI), which converts fructose-6-phosphate into mannose6-phosphate, a precursor of GDP-mannose, which is necessary for proper glycosylation. Through administration of mannose, this defect is elegantly bypassed and leads to a glycosylation pattern, which is almost completely normalized. Clinical symptoms greatly improve [63] as well, especially coagulation abnormalities and protein-losing enteropathy, bridging the defect and using hexokinase to deliver mannose to the glycosylation pathway [64]. Therapy seems to be more efficient in children than in adults, and adults might deliver some resistance to mannose supplementation (personal observation). Some of the clinical manifestations of PMI-deficiency, however, spontaneously improve with age, even without mannose therapy, especially the chronic diarrhea. It is hypothesized that this is due to up-regulation of the mannose transporter and increased activity of phosphoglucose isomerase, which has been described to catalyze the same reaction as the PMI enzyme [39,65]. Interestingly, in mannose-resistant cases, intravenous heparin therapy was found to be useful to treat the abnormal mucosal glycosylation in the bowels and improving symptoms in protein-losing enteropathy in adults [66]. A similar positive outcome has been reported in two young adults with PGM1-deficiency, who showed a mixed type I/type II pattern and decreased galactosylation by mass spectrometry. The patients experienced significant advancement of biochemical parameters and improvement of clinical features on galactose supplementation [57]. An interesting aspect of therapy in CDG is the use of acetylcholin-reuptake inhibitors in patients with DPAGT1-CDG. Although this is symptomatic treatment, and does not resolve the underlying metabolic defect, there is a significant improvement of the myasthenic features in children with DPAGT1-CDG. Unfortunately, these effects seem to diminish during the aging of the patients [29]. With respect to other CDG types, symptomatic treatment remains the treatment of choice in patients until more targeted treatments come available. One should emphasize, however, the specific need for treating osteoporosis and neuropathic pain in adults with CDG, especially in adult PMM2-CDG. Discussion
Unfortunately 25% of patients with CDG die in the first few years of life. The ones that survive were often diagnosed in childhood and are currently growing into adults, but also the ones diagnosed in adulthood frequently show a different phenotype. Examples include scoliosis, neuropathy and retina abnormalities in adult PMM2-CDG, myasthenia without CNS involvement in DPAGT1-CDG, liver cirrhosis in MPI-CDG, 221
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Wolthuis, Janssen, Cassiman, Lefeber & Morava-Kozicz
primary muscle presentation on PGM1-CDG and so on, (for specific features see bold features in TABLE 1) [7,40,57,60]. Once the patient reaches adulthood, CDG can be non-progressive, but patients rarely reach independence [39,67]. The wide variety of clinical presentation and disease severity in adults is the best described common CDG form – PMM2-CDG (SUPPLEMENTARY FIGURE 1). The phenotypic spectrum of PMM2-CDG keeps expanding, particularly at the less severe end where even patients with a normal cognitive function have been described [36]. Interestingly, diagnosis in this form can also be delayed to adult age [67]. Although adult patients with CDG hardly ever are symptom-free in childhood, the symptoms of DPAGT1-CDG, however, may begin only in adulthood [7]. Importantly, when CDG manifests as isolated symptoms and malformations, like a congenital cardiac malformation, or speech delay and intellectual disability, instead of a systemic disease, a late diagnosis is more likely. Concluding, the features of adult CDG patients may differ from the classical phenotype, as it is described in children. We propose to include CDG in the differential diagnosis in adults with unexplained neurologic symptoms and non-progressive intellectual disability, especially in association with hormonal or hemostatic abnormalities. Additional to the classic syndromal presentation with cerebellar vermis ataxia, facial dysmorphism and abnormal fat distribution, diverse congenital malformations are present in different types of CDG. The presence of unique malformations like congenital heart disease (Tetralogy of Fallot or VSD), eye malformations, like coloboma, distal limb reduction, skeletal dysplasia or palatoschisis in others might be responsible for the fact that several cases with CDG remain
undiagnosed to adulthood. The absence of neurologic disease in some CDG patients or mild learning disorder makes the diagnosis also difficult. For diagnostic testing, routine CDG screening could be applied as a first step, knowing that the TIEF may fail. However, if normal, more sensitive methods like mass spectrometry could be applied or direct testing of enzymes or genes. Expert commentary & five-year view
Glycosylation is a dynamic metabolic process, which is present in all cell compartments and essential in almost all functional aspects of the human body. It plays a role in organ development to metabolism; brain function; transport; signaling and immune, endocrine and stress response. The number of adults reported with N-linked glycosylation is close to a hundred, diagnosed with 18 different forms of N-glycosylation defects, mostly presenting with intellectual disability and neurologic symptoms. CDG forms a heterogeneous group. There are almost 100 distinct metabolic defects affecting glycosylation. New disorders are discovered almost monthly, making glycosylation one of the most common metabolic pathways involved in syndromal inborn errors of metabolism. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Most patients with congenital disorders of N-glycosylation (CDG) with abnormal N-glycosylation are diagnosed in the pediatric age and a multisystem presentation. • N-linked CDG leads to early death in about 25% of the patients. • Most children with CDG without multisystem involvement reach adulthood. • The common adult phenotype involves intellectual disability, speech disorder, visual loss, neuropathy and ataxia. • Systemic involvement in adult includes scoliosis, cataract and episodes of venous thromboses. • New types of CDGs have been defined in adults with isolated neurologic phenotype or intellectual disability. • In adult patients, CDG screening can be near-normal, hampering the diagnosis. • Due to congenital malformations, CDG cases might remain undiagnosed until adulthood.
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