Congenital Ichthyosis With Spastic Paraplegia of Adult Onset James O. McNamara, MD; John R. Curran, MD; Hideo H. \s=b\ Two
siblings had what we believe to unique disorder manifested by stationary congenital ichthyosiform erythroderma coupled with a slowly progressive spastic weakness of adult onset. The disorder was presumably inherited as an aube
a
tosomal recessive trait. The mechanism by which a genetic mutation would mediate this multiple organ system disorder is unknown. (Arch Neurol 32:699-701, 1975)
neurologic Several ichthyosis. 1920,
disorders are known to be associated with Henrichs1 disIn cribed a number of families with a high association of ichthyosis, psycho¬ sis, and mental retardation. Seven years later Rud2 reported a patient with ichthyosis, dwarfism, genital at¬
rophy, tetany, epilepsy, polyneuritis, and hyperchromic macrocytic anemia. The case report notwithstanding, Rud syndrome is generally considered to consist of
triad of mental retarda¬ tion, epilepsy, and ichthyosis. The en¬ tity known as Sjögren-Larsson syn¬ drome was probably first described in 1932 by Pardo-Castello and Faz3 who noted the association of ichthyosis with Little disease. In 1957 Sjögren and Larsson4 reported 29 patients with congenital ichthyosiform erythroderma of whom 24 had mental retardation as well as a pronounced motor deficit. The motor defect was typical of Little disease with nonAccepted
a
publication Jan 3, 1975. departments of neurology and pathology, University of Michigan Medical Center, for
From the
Ann Arbor. Dr McNamara is now at Duke University Medical Center, Durham, NC; Dr Curran is in Nampa, Idaho; and Dr Itabashi is at UCLA School of Medicine, Torrance, Calif. Reprint requests to Box M2900, Division of Neurology, Duke University Medical Center, Durham, NC 27710 (Dr McNamara).
Itabashi,
MD
weakness (legs than or greater arms) gait difficulties or both manifested in infancy or soon thereafter. In only four of these pa¬ tients was there any suggestion of progression of the motor deficit. In the remaining five of the 29 patients described, four died before the age of 3 years and no information was avail¬ able regarding their neurologic state. The sole remaining patient had men¬ tal retardation but no spasticity. Refsum disease is mainly charac¬ terized by chronic progressive polyneuropathy with weakness, ataxia, atypical retinitis pigmentosa, and other less constant associated find¬ ings, including ichthyosis, as well as deafness, anosmia, miosis, and skele¬ tal defects.5 The biochemical abnor¬ mality responsible for this syndrome is a defective alpha-oxidation of phytanic acid.6 The characteristic lab¬ oratory findings are increased spinal fluid protein and phytanic acid in se¬ rum and tissues. The purpose of this report is to de¬ scribe two siblings who have what we believe to be a unique syndrome of congenital ichthyosis, low normal in¬ telligence, and progressive spastic weakness of adult onset.
progressive spastic
REPORT OF CASES Case 1.—A 53-year-old housewife was re¬ ferred for evaluation of weakness. Aside from her congenital ichthyosis she was well until age 42 when she noted the in¬ sidious onset and gradual progression of leg weakness. For the two years prior to admission she had experienced episodic urinary incontinence primarily related to stress. A childhood injury resulted in per¬ manent blindness of the left eye. Results of a myelogram in 1958 and a left carotid arteriogram in 1963 were reportedly nor¬ mal. The remainder of her neurologic his¬ tory was unremarkable.
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/20/2015
Systems review findings and past medi¬ cal history were essentially normal, except for the patient being "onion skinned" at birth. Aside from a similarly affected brother (case 2) there was no family his¬ tory of either skin or nervous system dis¬ ease. She had five normal siblings, and both parents died of vascular disease at advanced ages. The grandparents were of Irish and German descent, and there was no history of consanguinity in the family. She and her brother had been employed by a circus and displayed as the "alligatorskin people"; she also performed as a tight¬ rope walker. Abnormalities on physical examination were limited to the skin, eyes, and nervous system. Her skin was greatly thickened, and she had large, dry scales throughout, with the exception of her scalp, face, palms, and soles (Fig 1). All flexor joint surfaces, including the popliteal and antecubital fossae, were dry and scaling, while the skin of the face and scalp was tight but not scaly. The periorbital skin was so tight that it resulted in ectropia and incomplete lid closure. Corneal scars were present bi¬ laterally, with the one on the left side being larger and centrally located. Visual acuity was 20/70 OD, and light perception only OS. Results of cranial nerve examina¬ tion including the fundi were normal. Her verbal intelligence quotient on a Wechsler Adult Intelligence Scale (WAIS) was 77, but the interpretation of these results was subject to error because of the patient's complete lack of formal education. Motor examination gave normal results except for moderate weakness of all muscles of the right arm and both legs. Sensory ex¬ amination disclosed reduced light touch and profoundly impaired position, vibra¬ tion, and deep pain sensation of the right side. These modalities were normal or only minimally impaired on the left side. Saddle area sensation was intact. Muscle stretch reflexes were 2+ to 3+ and symmetrical except for an absent right ankle jerk. Bi¬ lateral Babinski signs were present. De¬ spite the use of a walker, she had great difficulty ambulating.
Results of routine laboratory studies within normal limits including tests for syphilis and muscle enzymes. There was a mild increase of the alpha 1 fraction on serum protein electrophoresis and immunodiffusion disclosed a diffuse increase in IgA with normal levels of IgM and IgG. Karyotyping was normal as were serum phytanic acid and BI2 levels. Levels of urine ferric chloride, dinitrophenylhydrawere
zine, cyanide-nitroprusside, aryl sulfatase, and amino acid
screen were
normal. Re-
Fig 1.—Generalized ichthyosis portion of abdomen (case 1).
visible
over arms
a glucose tolerance test were mildly abnormal. Spinal fluid analysis showed 4 mononuclear cells per cubic mil¬ limeter, total protein level of 52 mg/100 ml, negative VDRL test for syphilis, and a colloidal gold curve of 0012210000. Brain scan and electroencephalogram were nor¬ mal. Chest and complete spine x-ray films were essentially normal. Skull x-ray films disclosed a calcified pineal gland deviated 2.5 mm from left to right. Electromyographic (EMG) examination of the right deltoid was normal but fibril¬ lations and positive waves were noted in the right first dorsal interosseous, left quadriceps femoris, anterior tibial, and ex¬ tensor digitorum brevis muscles. Motor conduction velocity of the right ulnar nerve was normal but the left peroneal nerve could not be stimulated. Biopsy of the right gastrocnemius muscle showed small clusters of small, angular muscle fibers randomly scattered through the fascicles. There was mild, intrafascicular fatty replacement but no sar¬ coplasmic degeneration. The findings were compatible with mild, long-standing neu¬
suits of
rogenic atrophy.
Case 2.—Aside from his congenital ich¬ the patient was well until age 42 when he noted the onset of tingling on the left side of his face. This remitted after several weeks. Two years later his right leg gradually became weak and he subse¬
thyosis,
quently developed a progressive quadri¬ plegia. He developed urinary incontinence two years prior to admission and remained incontinent thereafter. Aside from a posi¬ tive Lhermitte sign in the past, there were no other neurologic symptoms. Following development of leg weakness at age 44, he underwent a diagnostic work-up, including cervical myelography, the results of which
and
exposed
Fig 2.—Generalized Ichthyosis. Face and there is scalp hair loss (case 2).
normal. Past medical his¬ unremarkable except for a per¬ tory manent loss of scalp hair following treat¬ ment of the ichthyosis at age 8. Abnormalities in physical examination were limited to the eyes, nervous system, and skin. The dermatologie findings were identical to those in case 1 (Fig 2). There were large corneal scars on both eyes, and the visual acuity was 2/100 OD and light perception only OS. Examination of the cranial nerves was normal except for occa¬ sional dissociated nystagmus on horizontal gaze bilaterally and minimal limitation of upward gaze. Verbal IQ on a WAIS was 73, but this interpretation was subject to the same liabilities as that of his sister's (case 1). There was normal bulk, tone, and coor¬ dination of his arms but weakness was present in all muscle groups. The legs were spastic. No voluntary movement was de¬ tected. Light touch, pinprick, deep pain, and position sense were intact throughout, although position sense was reduced in the great toes. Responses to vibration were in¬ consistent. The triceps, biceps, and bra¬ chioradialis reflexes were 3+, 2+, and 0, respectively, on the right side and 2 +, 2 +, and 0, respectively, on the left. The knee jerks were 3 +. Sustained ankle clonus and bilateral Babinski signs were present. The patient was unable to walk even with me¬ chanical aid. All of the laboratory studies reported for case 1 were normal in case 2 with the fol¬ lowing exceptions. Two fasting blood glu¬ cose tests, the pre-/3 band on lipoprotein electrophoresis, and serum triglycérides were mildly elevated. Serum protein elec¬ trophoresis disclosed a slight increase in the alpha-1 fraction. Serum immunodiffusion showed a diffuse increase of IgA and IgM. Spinal fluid analysis demon-
were
reportedly
was
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/20/2015
scalp
are
spared,
but
strated 6,800 red blood cells and 2 mononu¬ clear cells per cubic millimeter (traumatic tap), total protein level of 52 mg/100 ml, negative VDRL test for syphilis, and col¬ loidal gold curve. Chest, skull, and com¬ plete spine x-ray films and EEG were essentially normal. Motor conduction veloc¬ ities of ulnar and median nerves in both arms were normal, as was an EMG of all four extremities except for a few fibrilla¬ tions and positive waves in muscles sup¬ plied by the left ulnar nerve. A cystometregram disclosed a mixed neurogenic bladder with uninhibited and motor par¬
alytic components. A skin biopsy specimen from the left calf showed changes consistent with lamel¬ lar type of nonbullous ichthyosis. There was moderate thickening of the horny layer and mild acanthosis was seen in the elongated rete ridges. Increased numbers of capillaries in each dermal papilla were sometimes surrounded by elongated rete ridges. No inflammatory or bullous changes were present. Paraffin-embedded sections of the left gastrocnemius muscle biopsy specimen showed marked disrup¬ tion of the usual fascicular pattern by marked perifascicular and intrafascicular fatty infiltration but only a relatively mi¬ nor increase in collagen. There was wide, abnormal variation in muscle fiber diame¬ angular fibers randomly in¬ terposed between hypertrophied fibers; the latter sometimes contained one to three in¬ ternal nuclei. Occasional vacuolated and necrotic muscle fibers were seen. Based on ter with small
the findings were con¬ sistent with a chronic end-stage process. Histologie features of both myopathie and neurogenic atrophy precluded a definitive diagnosis, but the prominence of small, angulated fibers and the relative absence
morphology alone,
sarcoplasmic changes favored the neu¬ rogenic component. A biopsy specimen of the sural nerve, stained with hematoxylineosin, Luxol fast blue, Bodian, and triof
chome methods
was
normal.
COMMENT We believe that these two patients have a unique congenital disorder manifested by stationary congenital
ichthyosiform erythroderma coupled a slowly progressive spastic quadriplegia of adult onset. While the patients resemble those described by Sjögren and Larsson, they differ in important respects. The patients de¬ scribed by Sjögren and Larsson had severe mental impairment (IQ of 50 or less) evident early in life, whereas our patients' intelligence was slightly with
below the normal range. Their pa¬ tients showed a motor deficit in in¬ fancy, whereas ours had normal mo¬ tor function until middle age, as emphasized by the first patient's his¬ tory of tightrope walking. Finally, there was little evidence to suggest that Sjögren and Larsson's patients suffered from a progressive neuro¬ logic disorder, whereas our patients have deteriorated since they first be¬ came
symptomatic.
The presence of
some
clinical find¬
ings suggesting peripheral neuropa¬ thy in combination with histopathologic features considered indicative of chronic myopathy warrants further comment. Drachman et al7 have de¬
scribed histologie findings character¬ istic of myopathy in patients with chronic neuropathic disease; they have also reported mixed myopathie and neuropathic findings in this same patient population. Both of our pa¬ tients had mild clinical manifesta¬ tions of carbohydrate intolerance. Thus, it is possible that the clinical findings of peripheral neuropathy and myopathie features found in one of the biopsy specimens may be ex¬ plained on the basis of a long-stand¬ ing, mild diabetic peripheral neuropa¬ thy. The possibility remains that the same disease process responsible for the central nervous system abnormal¬ ities caused the peripheral nerve and muscle pathologic findings. The possi¬ bility that the muscular changes are
secondary
to
an
upper motor
neuron
lesion remains speculative. The pronounced sensory abnormal¬ ities noted particularly in the first pa¬ tient are also of interest. While the minimal impairment of position sense present in the second patient may be attributable to a peripheral neuropa¬ thy, the first patient's impairment of all sensory modalities on the right side, including the face, with only minimal impairment of vibration sense on the left suggests a lesion in¬ volving sensory tracts high in the left side of the brain stem or the thala¬ mus. Such a lesion would most likely be due to the same pathologic process responsible for the remainder of her
neurologic deficits, although hysteria possibly account for such a hemisensory defect. In the cases of Sjögren and Larsson, the results of could
multiple organ system disorder is speculative. Among a large number of possible mechanisms are the fol¬ lowing: (1) a diffuse membrane dis¬ order associated with multisystem degenerative disease (eg, myotonic dystrophy)13; (2) an enzymatic defect associated with a multisystem degen¬ erative disease (eg, Refsum disease); and (3) a genetically determined, se¬ lective immune defect predisposing to a "slow virus" infection and thereby accounting for the nervous system disease (eg, a proposed model for the pathogenesis of multiple sclerosis).14 These various possibilities are not necessarily mutually exclusive. Elaine M. Jones and Karen A. Case assisted with the manuscript, and Allen D. Roses, MD, gave advice and criticism.
sensory examination when mentioned
normal. The elevated serum IgA values noted here also deserve further com¬ ment. Immunoglobulin abnormalities have been reported in association with a number of neurologic disease, including hereditary sensory neurop¬ were
athy (increased IgA),8 myotonic dys¬ trophy (decreased IgA),9 and ataxia telangiectasia (decreased IgA and
IgE).'011 However, increased serum IgA levels appear to be a common phenomenon in a variety of skin dis¬ orders, although this has not been de¬ scribed specifically in association with ichthyosis, to the best of our knowl¬ edge.12 Considering these patients' marked skin involvement, we think that this is the most likely explana¬ tion of the IgA elevation. The possi¬ bility remains that this finding re¬ flects an immunologie disorder that is directly related to the nervous system disease or that it is an independent
manifestation of the fundamental disorder afflicting these patients. Finally, regarding the pathogen¬ esis of this disorder, it is possible that this constellation of findings occurred in these two siblings by chance alone, but it seems more likely that there is a common factor to account for their association. We believe the most likely explanation is that this entity was inherited as an autosomal reces¬ sive trait. The mechanism by which a genetic mutation would mediate this
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References 1. Henrichs J: Sindslidelser og Hereditaere Hudanomalier Saerlig Ichthyose. Nor Mag Lagevidensk 11:996, 1920. 2. Rud E: Et tilfaelde af infantilsme med tetani, epilepsy, polvneuritis, ichthyosis og anaemi af pernicios type. Hospitalstidende 70:525-538, 1927. 3. Pardo-Castello V, Faz H: Ichthyosis: Little's disease. Arch Dermatol 26:915, 1932. 4. Sj\l=o"\grenT, Larsson T: Oligophrenia in combination with congenital ichthyosis and spastic disorders: A clinical and genetic study. Acta Psychiatr Neurol Scand 32 (suppl 113):1-112, 1957. 5. Refsum S: Heredopathia atactica polyneuritiformis: Familial syndrome not hitherto described; contribution to clinical study of hereditary diseases of nervous system. Acta Psychiatr Neurol Scand 21 (suppl 38):1-303, 1946. 6. Herndon JH Jr, Steinberg D, Uhlendorf BW: Refsum's disease: Characterization of the enzyme defect in cell cultures. J Clin Invest 48:1017-1032, 1969. 7. Drachman DB, Murphy SR, Migan MP, et al: "Myopathic" changes in chronically denervated muscles. Arch Neurol 16:14-24, 1967. 8. Whitaker JN, Falchuck ZM, Engel WK, et al: Hereditary sensory neuropathy. Arch Neurol 30:359-371, 1974. 9. Engel WK, McFarlin DE, Drews GA, et al: Protein abnormalities in neuromuscular diseases: Part 1. JAMA 195:754-760, 1966. 10. Young RR, Austen KF, Moser HW: Abnormalities of serum \g=g\-1-Aglobulin and ataxia telangiectasia. Medicine 43:423-433, 1964. 11. Ammann AJ, Cain WA, Ishizaka K, et al: Immunoglobulin E deficiency in ataxia telangiectasia. N Engl J Med 281:469-472, 1969. 12. Faser NG, Dick HM, Crichton WB: Immunoglobulins in dermatitis herpetiformis and various other skin diseases. Br J Dermatol 81:89\x=req-\ 95, 1969. 13. Roses AD, Appel SH: Muscle membrane protein kinase in myotonic dystrophy. Nature
250:245-247,
1974. 14. Measles and multiple Lancet 1:247-249, 1974.
sclerosis, editorial.
siblings had what we believe to unique disorder manifested by stationary congenital ichthyosiform erythroderma coupled with a slowly progressive spastic weakness of adult onset. The disorder was presumably inherited as an aube
a
tosomal recessive trait. The mechanism by which a genetic mutation would mediate this multiple organ system disorder is unknown. (Arch Neurol 32:699-701, 1975)
neurologic Several ichthyosis. 1920,
disorders are known to be associated with Henrichs1 disIn cribed a number of families with a high association of ichthyosis, psycho¬ sis, and mental retardation. Seven years later Rud2 reported a patient with ichthyosis, dwarfism, genital at¬
rophy, tetany, epilepsy, polyneuritis, and hyperchromic macrocytic anemia. The case report notwithstanding, Rud syndrome is generally considered to consist of
triad of mental retarda¬ tion, epilepsy, and ichthyosis. The en¬ tity known as Sjögren-Larsson syn¬ drome was probably first described in 1932 by Pardo-Castello and Faz3 who noted the association of ichthyosis with Little disease. In 1957 Sjögren and Larsson4 reported 29 patients with congenital ichthyosiform erythroderma of whom 24 had mental retardation as well as a pronounced motor deficit. The motor defect was typical of Little disease with nonAccepted
a
publication Jan 3, 1975. departments of neurology and pathology, University of Michigan Medical Center, for
From the
Ann Arbor. Dr McNamara is now at Duke University Medical Center, Durham, NC; Dr Curran is in Nampa, Idaho; and Dr Itabashi is at UCLA School of Medicine, Torrance, Calif. Reprint requests to Box M2900, Division of Neurology, Duke University Medical Center, Durham, NC 27710 (Dr McNamara).
Itabashi,
MD
weakness (legs than or greater arms) gait difficulties or both manifested in infancy or soon thereafter. In only four of these pa¬ tients was there any suggestion of progression of the motor deficit. In the remaining five of the 29 patients described, four died before the age of 3 years and no information was avail¬ able regarding their neurologic state. The sole remaining patient had men¬ tal retardation but no spasticity. Refsum disease is mainly charac¬ terized by chronic progressive polyneuropathy with weakness, ataxia, atypical retinitis pigmentosa, and other less constant associated find¬ ings, including ichthyosis, as well as deafness, anosmia, miosis, and skele¬ tal defects.5 The biochemical abnor¬ mality responsible for this syndrome is a defective alpha-oxidation of phytanic acid.6 The characteristic lab¬ oratory findings are increased spinal fluid protein and phytanic acid in se¬ rum and tissues. The purpose of this report is to de¬ scribe two siblings who have what we believe to be a unique syndrome of congenital ichthyosis, low normal in¬ telligence, and progressive spastic weakness of adult onset.
progressive spastic
REPORT OF CASES Case 1.—A 53-year-old housewife was re¬ ferred for evaluation of weakness. Aside from her congenital ichthyosis she was well until age 42 when she noted the in¬ sidious onset and gradual progression of leg weakness. For the two years prior to admission she had experienced episodic urinary incontinence primarily related to stress. A childhood injury resulted in per¬ manent blindness of the left eye. Results of a myelogram in 1958 and a left carotid arteriogram in 1963 were reportedly nor¬ mal. The remainder of her neurologic his¬ tory was unremarkable.
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/20/2015
Systems review findings and past medi¬ cal history were essentially normal, except for the patient being "onion skinned" at birth. Aside from a similarly affected brother (case 2) there was no family his¬ tory of either skin or nervous system dis¬ ease. She had five normal siblings, and both parents died of vascular disease at advanced ages. The grandparents were of Irish and German descent, and there was no history of consanguinity in the family. She and her brother had been employed by a circus and displayed as the "alligatorskin people"; she also performed as a tight¬ rope walker. Abnormalities on physical examination were limited to the skin, eyes, and nervous system. Her skin was greatly thickened, and she had large, dry scales throughout, with the exception of her scalp, face, palms, and soles (Fig 1). All flexor joint surfaces, including the popliteal and antecubital fossae, were dry and scaling, while the skin of the face and scalp was tight but not scaly. The periorbital skin was so tight that it resulted in ectropia and incomplete lid closure. Corneal scars were present bi¬ laterally, with the one on the left side being larger and centrally located. Visual acuity was 20/70 OD, and light perception only OS. Results of cranial nerve examina¬ tion including the fundi were normal. Her verbal intelligence quotient on a Wechsler Adult Intelligence Scale (WAIS) was 77, but the interpretation of these results was subject to error because of the patient's complete lack of formal education. Motor examination gave normal results except for moderate weakness of all muscles of the right arm and both legs. Sensory ex¬ amination disclosed reduced light touch and profoundly impaired position, vibra¬ tion, and deep pain sensation of the right side. These modalities were normal or only minimally impaired on the left side. Saddle area sensation was intact. Muscle stretch reflexes were 2+ to 3+ and symmetrical except for an absent right ankle jerk. Bi¬ lateral Babinski signs were present. De¬ spite the use of a walker, she had great difficulty ambulating.
Results of routine laboratory studies within normal limits including tests for syphilis and muscle enzymes. There was a mild increase of the alpha 1 fraction on serum protein electrophoresis and immunodiffusion disclosed a diffuse increase in IgA with normal levels of IgM and IgG. Karyotyping was normal as were serum phytanic acid and BI2 levels. Levels of urine ferric chloride, dinitrophenylhydrawere
zine, cyanide-nitroprusside, aryl sulfatase, and amino acid
screen were
normal. Re-
Fig 1.—Generalized ichthyosis portion of abdomen (case 1).
visible
over arms
a glucose tolerance test were mildly abnormal. Spinal fluid analysis showed 4 mononuclear cells per cubic mil¬ limeter, total protein level of 52 mg/100 ml, negative VDRL test for syphilis, and a colloidal gold curve of 0012210000. Brain scan and electroencephalogram were nor¬ mal. Chest and complete spine x-ray films were essentially normal. Skull x-ray films disclosed a calcified pineal gland deviated 2.5 mm from left to right. Electromyographic (EMG) examination of the right deltoid was normal but fibril¬ lations and positive waves were noted in the right first dorsal interosseous, left quadriceps femoris, anterior tibial, and ex¬ tensor digitorum brevis muscles. Motor conduction velocity of the right ulnar nerve was normal but the left peroneal nerve could not be stimulated. Biopsy of the right gastrocnemius muscle showed small clusters of small, angular muscle fibers randomly scattered through the fascicles. There was mild, intrafascicular fatty replacement but no sar¬ coplasmic degeneration. The findings were compatible with mild, long-standing neu¬
suits of
rogenic atrophy.
Case 2.—Aside from his congenital ich¬ the patient was well until age 42 when he noted the onset of tingling on the left side of his face. This remitted after several weeks. Two years later his right leg gradually became weak and he subse¬
thyosis,
quently developed a progressive quadri¬ plegia. He developed urinary incontinence two years prior to admission and remained incontinent thereafter. Aside from a posi¬ tive Lhermitte sign in the past, there were no other neurologic symptoms. Following development of leg weakness at age 44, he underwent a diagnostic work-up, including cervical myelography, the results of which
and
exposed
Fig 2.—Generalized Ichthyosis. Face and there is scalp hair loss (case 2).
normal. Past medical his¬ unremarkable except for a per¬ tory manent loss of scalp hair following treat¬ ment of the ichthyosis at age 8. Abnormalities in physical examination were limited to the eyes, nervous system, and skin. The dermatologie findings were identical to those in case 1 (Fig 2). There were large corneal scars on both eyes, and the visual acuity was 2/100 OD and light perception only OS. Examination of the cranial nerves was normal except for occa¬ sional dissociated nystagmus on horizontal gaze bilaterally and minimal limitation of upward gaze. Verbal IQ on a WAIS was 73, but this interpretation was subject to the same liabilities as that of his sister's (case 1). There was normal bulk, tone, and coor¬ dination of his arms but weakness was present in all muscle groups. The legs were spastic. No voluntary movement was de¬ tected. Light touch, pinprick, deep pain, and position sense were intact throughout, although position sense was reduced in the great toes. Responses to vibration were in¬ consistent. The triceps, biceps, and bra¬ chioradialis reflexes were 3+, 2+, and 0, respectively, on the right side and 2 +, 2 +, and 0, respectively, on the left. The knee jerks were 3 +. Sustained ankle clonus and bilateral Babinski signs were present. The patient was unable to walk even with me¬ chanical aid. All of the laboratory studies reported for case 1 were normal in case 2 with the fol¬ lowing exceptions. Two fasting blood glu¬ cose tests, the pre-/3 band on lipoprotein electrophoresis, and serum triglycérides were mildly elevated. Serum protein elec¬ trophoresis disclosed a slight increase in the alpha-1 fraction. Serum immunodiffusion showed a diffuse increase of IgA and IgM. Spinal fluid analysis demon-
were
reportedly
was
Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/20/2015
scalp
are
spared,
but
strated 6,800 red blood cells and 2 mononu¬ clear cells per cubic millimeter (traumatic tap), total protein level of 52 mg/100 ml, negative VDRL test for syphilis, and col¬ loidal gold curve. Chest, skull, and com¬ plete spine x-ray films and EEG were essentially normal. Motor conduction veloc¬ ities of ulnar and median nerves in both arms were normal, as was an EMG of all four extremities except for a few fibrilla¬ tions and positive waves in muscles sup¬ plied by the left ulnar nerve. A cystometregram disclosed a mixed neurogenic bladder with uninhibited and motor par¬
alytic components. A skin biopsy specimen from the left calf showed changes consistent with lamel¬ lar type of nonbullous ichthyosis. There was moderate thickening of the horny layer and mild acanthosis was seen in the elongated rete ridges. Increased numbers of capillaries in each dermal papilla were sometimes surrounded by elongated rete ridges. No inflammatory or bullous changes were present. Paraffin-embedded sections of the left gastrocnemius muscle biopsy specimen showed marked disrup¬ tion of the usual fascicular pattern by marked perifascicular and intrafascicular fatty infiltration but only a relatively mi¬ nor increase in collagen. There was wide, abnormal variation in muscle fiber diame¬ angular fibers randomly in¬ terposed between hypertrophied fibers; the latter sometimes contained one to three in¬ ternal nuclei. Occasional vacuolated and necrotic muscle fibers were seen. Based on ter with small
the findings were con¬ sistent with a chronic end-stage process. Histologie features of both myopathie and neurogenic atrophy precluded a definitive diagnosis, but the prominence of small, angulated fibers and the relative absence
morphology alone,
sarcoplasmic changes favored the neu¬ rogenic component. A biopsy specimen of the sural nerve, stained with hematoxylineosin, Luxol fast blue, Bodian, and triof
chome methods
was
normal.
COMMENT We believe that these two patients have a unique congenital disorder manifested by stationary congenital
ichthyosiform erythroderma coupled a slowly progressive spastic quadriplegia of adult onset. While the patients resemble those described by Sjögren and Larsson, they differ in important respects. The patients de¬ scribed by Sjögren and Larsson had severe mental impairment (IQ of 50 or less) evident early in life, whereas our patients' intelligence was slightly with
below the normal range. Their pa¬ tients showed a motor deficit in in¬ fancy, whereas ours had normal mo¬ tor function until middle age, as emphasized by the first patient's his¬ tory of tightrope walking. Finally, there was little evidence to suggest that Sjögren and Larsson's patients suffered from a progressive neuro¬ logic disorder, whereas our patients have deteriorated since they first be¬ came
symptomatic.
The presence of
some
clinical find¬
ings suggesting peripheral neuropa¬ thy in combination with histopathologic features considered indicative of chronic myopathy warrants further comment. Drachman et al7 have de¬
scribed histologie findings character¬ istic of myopathy in patients with chronic neuropathic disease; they have also reported mixed myopathie and neuropathic findings in this same patient population. Both of our pa¬ tients had mild clinical manifesta¬ tions of carbohydrate intolerance. Thus, it is possible that the clinical findings of peripheral neuropathy and myopathie features found in one of the biopsy specimens may be ex¬ plained on the basis of a long-stand¬ ing, mild diabetic peripheral neuropa¬ thy. The possibility remains that the same disease process responsible for the central nervous system abnormal¬ ities caused the peripheral nerve and muscle pathologic findings. The possi¬ bility that the muscular changes are
secondary
to
an
upper motor
neuron
lesion remains speculative. The pronounced sensory abnormal¬ ities noted particularly in the first pa¬ tient are also of interest. While the minimal impairment of position sense present in the second patient may be attributable to a peripheral neuropa¬ thy, the first patient's impairment of all sensory modalities on the right side, including the face, with only minimal impairment of vibration sense on the left suggests a lesion in¬ volving sensory tracts high in the left side of the brain stem or the thala¬ mus. Such a lesion would most likely be due to the same pathologic process responsible for the remainder of her
neurologic deficits, although hysteria possibly account for such a hemisensory defect. In the cases of Sjögren and Larsson, the results of could
multiple organ system disorder is speculative. Among a large number of possible mechanisms are the fol¬ lowing: (1) a diffuse membrane dis¬ order associated with multisystem degenerative disease (eg, myotonic dystrophy)13; (2) an enzymatic defect associated with a multisystem degen¬ erative disease (eg, Refsum disease); and (3) a genetically determined, se¬ lective immune defect predisposing to a "slow virus" infection and thereby accounting for the nervous system disease (eg, a proposed model for the pathogenesis of multiple sclerosis).14 These various possibilities are not necessarily mutually exclusive. Elaine M. Jones and Karen A. Case assisted with the manuscript, and Allen D. Roses, MD, gave advice and criticism.
sensory examination when mentioned
normal. The elevated serum IgA values noted here also deserve further com¬ ment. Immunoglobulin abnormalities have been reported in association with a number of neurologic disease, including hereditary sensory neurop¬ were
athy (increased IgA),8 myotonic dys¬ trophy (decreased IgA),9 and ataxia telangiectasia (decreased IgA and
IgE).'011 However, increased serum IgA levels appear to be a common phenomenon in a variety of skin dis¬ orders, although this has not been de¬ scribed specifically in association with ichthyosis, to the best of our knowl¬ edge.12 Considering these patients' marked skin involvement, we think that this is the most likely explana¬ tion of the IgA elevation. The possi¬ bility remains that this finding re¬ flects an immunologie disorder that is directly related to the nervous system disease or that it is an independent
manifestation of the fundamental disorder afflicting these patients. Finally, regarding the pathogen¬ esis of this disorder, it is possible that this constellation of findings occurred in these two siblings by chance alone, but it seems more likely that there is a common factor to account for their association. We believe the most likely explanation is that this entity was inherited as an autosomal reces¬ sive trait. The mechanism by which a genetic mutation would mediate this
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References 1. Henrichs J: Sindslidelser og Hereditaere Hudanomalier Saerlig Ichthyose. Nor Mag Lagevidensk 11:996, 1920. 2. Rud E: Et tilfaelde af infantilsme med tetani, epilepsy, polvneuritis, ichthyosis og anaemi af pernicios type. Hospitalstidende 70:525-538, 1927. 3. Pardo-Castello V, Faz H: Ichthyosis: Little's disease. Arch Dermatol 26:915, 1932. 4. Sj\l=o"\grenT, Larsson T: Oligophrenia in combination with congenital ichthyosis and spastic disorders: A clinical and genetic study. Acta Psychiatr Neurol Scand 32 (suppl 113):1-112, 1957. 5. Refsum S: Heredopathia atactica polyneuritiformis: Familial syndrome not hitherto described; contribution to clinical study of hereditary diseases of nervous system. Acta Psychiatr Neurol Scand 21 (suppl 38):1-303, 1946. 6. Herndon JH Jr, Steinberg D, Uhlendorf BW: Refsum's disease: Characterization of the enzyme defect in cell cultures. J Clin Invest 48:1017-1032, 1969. 7. Drachman DB, Murphy SR, Migan MP, et al: "Myopathic" changes in chronically denervated muscles. Arch Neurol 16:14-24, 1967. 8. Whitaker JN, Falchuck ZM, Engel WK, et al: Hereditary sensory neuropathy. Arch Neurol 30:359-371, 1974. 9. Engel WK, McFarlin DE, Drews GA, et al: Protein abnormalities in neuromuscular diseases: Part 1. JAMA 195:754-760, 1966. 10. Young RR, Austen KF, Moser HW: Abnormalities of serum \g=g\-1-Aglobulin and ataxia telangiectasia. Medicine 43:423-433, 1964. 11. Ammann AJ, Cain WA, Ishizaka K, et al: Immunoglobulin E deficiency in ataxia telangiectasia. N Engl J Med 281:469-472, 1969. 12. Faser NG, Dick HM, Crichton WB: Immunoglobulins in dermatitis herpetiformis and various other skin diseases. Br J Dermatol 81:89\x=req-\ 95, 1969. 13. Roses AD, Appel SH: Muscle membrane protein kinase in myotonic dystrophy. Nature
250:245-247,
1974. 14. Measles and multiple Lancet 1:247-249, 1974.
sclerosis, editorial.
