REFERENCES 4. Muthusamy K, Seidl AJ, Friesen RM, Carollo JJ, Pan
6. Perry J, Hoffer MM, Antonelli D, Plut J, Lewis G,
Z, Chang FM. Rectus femoris transfer in children
Greenberg R. Electromyography before and after surgery
2. Knuppe AE, Bishop NA, Clark AJ, Alderink GJ, Barr
with cerebral palsy: evaluation of transfer site and
for hip deformity in children with cerebral palsy. J Bone
KM, Miller AL. Prolonged swing phase rectus femoris
preoperative indicators. J Pediatr Orthop 2008; 28:
Joint Surg Am 1976; 58: 201–8.
activity is not associated with stiff-knee gait in children
674–8.
1. Perry J. Gait Analysis: Normal and Pathological Function. Thorofare, NJ: SLACK Inc, 1992: 95.
with cerebral palsy: a retrospective study of 407 limbs. Gait Posture 2013; 37: 345–8. 3. Kay RM, Rethlefsen SA, Kelly JP, Wren TA. Predictive value of the Duncan-Ely test in distal rectus femoris
5. Lee SY, Sung KH, Chung CY, et al. Reliability and validity of the Duncan-Ely test for assessing rectus femoris spasticity in patients with cerebral palsy. Dev Med Child Neurol 2015; 57: 963–8.
transfer. J Pediatr Orthop 2004; 24: 59–62.
GLUT1 deficiency syndrome and ketogenic diet therapies: missing rare but treatable diseases? JOERG KLEPPER Department of Pediatrics, Klinikum Aschaffenburg, Aschaffenburg, Germany. doi: 10.1111/dmcn.12807 This commentary is on the the original article by Schoeler et al. on pages 969–976 of this issue.
Every paediatrician recognizes that his/her knowledge of rare diseases is limited. We all share a substantial basic fear that we might miss a treatable disease in a complex patient. Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is such a disease. It is caused by impaired glucose transport into brain. The resulting brain energy crisis causes seizures, developmental delay, and movement abnormalities in children. It is diagnosed by isolated low cerebrospinal glucose and/or mutations in the SLC2A1 gene and can be treated very effectively by ketogenic diet therapies (KDT). These diets provide ketones as an alternative fuel to the brain, effectively controlling seizures and improving development.1 Schoeler et al.2 have investigated whether a positive response to KDT indicates undiagnosed GLUT1-DS. The condition was identified in 1 out of 246 participants (0.4%) by SLC2A1 gene analysis. However, 2 out of 246 participants (0.8%) without SLC2A1 mutations were seizure-free at every follow-up point and single-variant and gene burden association tests gave no significant results. The authors concluded that a favourable response to KDT is not solely explained by mutations in SLC2A1. The paper raises several important questions.
Is a favourable response to KDT a useful tool to identify undiagnosed GLUT1-DS? The answer is ‘yes’: in general it seems justified to consider rare but treatable diseases even if a single patient may benefit from the diagnosis. Also, Schoeler et al. based the
896 Developmental Medicine & Child Neurology 2015, 57: 890–8
diagnosis on SLC2A1-mutations alone: lumbar punctures were not performed in all cases. SLC2A1-negative variants presenting with isolated hypoglycorrachia may have remained undiagnosed. These patients exist – a recent report from Japan classified 4 out of 32 patients (12.5%) as SLC2A1-negative.3
Who will benefit from KDT? KDTs are established non-pharmacological therapies for intractable childhood epilepsy. The modified Atkins diet or the low glycemic index treatment have further improved compliance and effectiveness and have expanded KDT beyond childhood epilepsy into adult neurological and metabolic disease.4 KDT are the treatment of choice for GLUT1-DS and pyruvate dehydrogenase deficiency. Younger children respond better and increasing data indicates that in Dravet syndrome, tuberous sclerosis complex, and myoclonic astatic epilepsy, KDT appear especially beneficial. However, as stated in the article we are still lacking predictive parameters. What are the implications of this article? Clinical implications are threefold: (1) KDT are effective beyond GLUT1-DS; (2) consider GLUT1-DS when KDT are beneficial; and (3) the diagnosis of GLUT1-DS is based on hypoglycorrhachia and SLC2A1 mutations. Future research should focus on parameters indicating a favourable response to KDT. In SLC2A1-negative variants the potential disease mechanisms downstream of DNA mutations such as impaired mRNA splicing, protein assembly, transportation, intracellular storaging, and activation need to be investigated.5 Finally, it is about time to establish an international clinical classification of GLUT1-DS. In this context a patient databank recently established by UT Southwestern Medical Center, University of Texas will contribute to achieve this goal (www.g1dregistry.org).
REFERENCES 1. Leen WG, Klepper J, Verbeek MM, et al. Glucose
3. Ito Y, Takahashi S, Kagitani-Shimono K, et al. Nation-
5. Klepper J. Absence of SLC2A1 mutations does not
transporter-1 deficiency syndrome: the expanding clini-
wide survey of glucose transporter-1 deficiency syn-
exclude Glut1 deficiency syndrome. Neuropediatrics 2013;
cal and genetic spectrum of a treatable disorder. Brain
drome (GLUT-1DS) in Japan. Brain Dev 2014; pii:
44: 235–6.
2010; 133: 655–70.
S0387-7604(14)00267-8.
2. Schoeler NE, Cross JH, Drury S, et al. Favourable
4. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond
response to ketogenic dietary therapies: undiagnosed glu-
weight loss: a review of the therapeutic uses of very-
cose 1 transporter deficiency syndrome is only one factor.
low-carbohydrate (ketogenic) diets. Eur J Clin Nutr
Dev Med Child Neurol 2015; 57: 969–76.
2013; 67: 789–96.
Pathways to good hand function after early brain injury ANNA P BASU Institute of Neuroscience, Newcastle University, Newcastle, UK. doi: 10.1111/dmcn.12836 This commentary is on the case report by Fiori et al. on pages 977–980 of this issue.
Fiori et al.1 describe a left-handed adolescent with mirror movements and a fast corticospinal tract projection from the right motor cortex, influencing hand muscles bilaterally. Despite imaging evidence of an early left-sided white matter lesion and small left caudate, the patient did not have hemiplegia. The case is surprising in view of research indicating that after unilateral brain injury, a fast ipsilateral corticospinal tract projection from the undamaged hemisphere is associated with a relatively poor motor outcome.2–4 This occurs through progressive activity-dependent displacement of the remaining contralateral corticospinal tract projections from the damaged hemisphere. Although those with ipsilateral corticospinal tract projections from lesions sustained earlier in brain development generally (but not always) fare better, normal motor outcome has not previously been reported. The case raises interesting questions. Firstly, what constitutes good hand function? The patient, who was perceived to have ‘good motor control’, presented with mirror movements. These are involuntary contralateral, predominantly distal upper limb movements, occurring simultaneously with and ‘mirroring’ the voluntary movement. They can be attributed to bilateral or branched corticospinal tract projections or in some cases (such as physiological mirror movements during childhood) to insufficient callosal inhibition or poor motor planning.5 They can occur in unilateral spastic cerebral palsy, in certain syndromes (Kallmann syndrome, Klippel–Feil syndrome, etc.), or in isolation, sometimes with identified genetic causes such as DCC mutations. They are problematic, interfere with performance of asymmetrical bimanual tasks, and can lead to discomfort. Management is centred around developing appropriate strategies for activities of
daily living as there is currently no effective treatment, although neurophysiological approaches modulating interhemispheric inhibition are under exploration for certain forms of mirror movements. Pragmatically, the lack of demonstration of motor control problems in this patient indicates a general need for better clinical assessments of bimanual dexterity. Secondly, what forms of post-lesional motor system reorganization are compatible with a good motor outcome? In this patient the symmetry demonstrated at the level of the pons and the residual corticospinal tract projection suggest that all descending motor pathways were at least partially preserved. This likely includes contralateral corticospinal tract projections from the damaged hemisphere to muscles other than those tested in the study and accounts for the relatively good outcome. The authors suggest that damage to descending pathways other than the corticospinal tract contributes to the motor impairments in congenital hemiplegia. This is an interesting viewpoint: most articles consider the role of these pathways in recovery. The reticulospinal and vestibulospinal tracts, and propriospinal system are under active investigation in motor recovery after stroke6 but have been less well considered after early brain injury, when the corticospinal tract remains the main focus. There are major differences between the developing and established motor systems. The fast ipsilateral corticospinal tract projections sometimes seen from the contralesional hemisphere after early unilateral brain injury do not arise after stroke in adults. These fast ipsilateral corticospinal tract projections can clearly cause motor control problems through mirror movements and displacement of more functional contralateral projections, but might still have some functional role. In contrast there is no evidence that the ipsilateral corticospinal tract contributes to motor recovery after stroke in adults.6 Additionally, although the human rubrospinal tract is vestigial, it may play a more active role in early motor system development and therefore also in recovery after early brain injury.3 We need to investigate post-lesional changes in the reticulospinal, vestibulospinal, and propriospinal pathways in the context Commentaries
897
6. Perry J, Hoffer MM, Antonelli D, Plut J, Lewis G,
Z, Chang FM. Rectus femoris transfer in children
Greenberg R. Electromyography before and after surgery
2. Knuppe AE, Bishop NA, Clark AJ, Alderink GJ, Barr
with cerebral palsy: evaluation of transfer site and
for hip deformity in children with cerebral palsy. J Bone
KM, Miller AL. Prolonged swing phase rectus femoris
preoperative indicators. J Pediatr Orthop 2008; 28:
Joint Surg Am 1976; 58: 201–8.
activity is not associated with stiff-knee gait in children
674–8.
1. Perry J. Gait Analysis: Normal and Pathological Function. Thorofare, NJ: SLACK Inc, 1992: 95.
with cerebral palsy: a retrospective study of 407 limbs. Gait Posture 2013; 37: 345–8. 3. Kay RM, Rethlefsen SA, Kelly JP, Wren TA. Predictive value of the Duncan-Ely test in distal rectus femoris
5. Lee SY, Sung KH, Chung CY, et al. Reliability and validity of the Duncan-Ely test for assessing rectus femoris spasticity in patients with cerebral palsy. Dev Med Child Neurol 2015; 57: 963–8.
transfer. J Pediatr Orthop 2004; 24: 59–62.
GLUT1 deficiency syndrome and ketogenic diet therapies: missing rare but treatable diseases? JOERG KLEPPER Department of Pediatrics, Klinikum Aschaffenburg, Aschaffenburg, Germany. doi: 10.1111/dmcn.12807 This commentary is on the the original article by Schoeler et al. on pages 969–976 of this issue.
Every paediatrician recognizes that his/her knowledge of rare diseases is limited. We all share a substantial basic fear that we might miss a treatable disease in a complex patient. Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is such a disease. It is caused by impaired glucose transport into brain. The resulting brain energy crisis causes seizures, developmental delay, and movement abnormalities in children. It is diagnosed by isolated low cerebrospinal glucose and/or mutations in the SLC2A1 gene and can be treated very effectively by ketogenic diet therapies (KDT). These diets provide ketones as an alternative fuel to the brain, effectively controlling seizures and improving development.1 Schoeler et al.2 have investigated whether a positive response to KDT indicates undiagnosed GLUT1-DS. The condition was identified in 1 out of 246 participants (0.4%) by SLC2A1 gene analysis. However, 2 out of 246 participants (0.8%) without SLC2A1 mutations were seizure-free at every follow-up point and single-variant and gene burden association tests gave no significant results. The authors concluded that a favourable response to KDT is not solely explained by mutations in SLC2A1. The paper raises several important questions.
Is a favourable response to KDT a useful tool to identify undiagnosed GLUT1-DS? The answer is ‘yes’: in general it seems justified to consider rare but treatable diseases even if a single patient may benefit from the diagnosis. Also, Schoeler et al. based the
896 Developmental Medicine & Child Neurology 2015, 57: 890–8
diagnosis on SLC2A1-mutations alone: lumbar punctures were not performed in all cases. SLC2A1-negative variants presenting with isolated hypoglycorrachia may have remained undiagnosed. These patients exist – a recent report from Japan classified 4 out of 32 patients (12.5%) as SLC2A1-negative.3
Who will benefit from KDT? KDTs are established non-pharmacological therapies for intractable childhood epilepsy. The modified Atkins diet or the low glycemic index treatment have further improved compliance and effectiveness and have expanded KDT beyond childhood epilepsy into adult neurological and metabolic disease.4 KDT are the treatment of choice for GLUT1-DS and pyruvate dehydrogenase deficiency. Younger children respond better and increasing data indicates that in Dravet syndrome, tuberous sclerosis complex, and myoclonic astatic epilepsy, KDT appear especially beneficial. However, as stated in the article we are still lacking predictive parameters. What are the implications of this article? Clinical implications are threefold: (1) KDT are effective beyond GLUT1-DS; (2) consider GLUT1-DS when KDT are beneficial; and (3) the diagnosis of GLUT1-DS is based on hypoglycorrhachia and SLC2A1 mutations. Future research should focus on parameters indicating a favourable response to KDT. In SLC2A1-negative variants the potential disease mechanisms downstream of DNA mutations such as impaired mRNA splicing, protein assembly, transportation, intracellular storaging, and activation need to be investigated.5 Finally, it is about time to establish an international clinical classification of GLUT1-DS. In this context a patient databank recently established by UT Southwestern Medical Center, University of Texas will contribute to achieve this goal (www.g1dregistry.org).
REFERENCES 1. Leen WG, Klepper J, Verbeek MM, et al. Glucose
3. Ito Y, Takahashi S, Kagitani-Shimono K, et al. Nation-
5. Klepper J. Absence of SLC2A1 mutations does not
transporter-1 deficiency syndrome: the expanding clini-
wide survey of glucose transporter-1 deficiency syn-
exclude Glut1 deficiency syndrome. Neuropediatrics 2013;
cal and genetic spectrum of a treatable disorder. Brain
drome (GLUT-1DS) in Japan. Brain Dev 2014; pii:
44: 235–6.
2010; 133: 655–70.
S0387-7604(14)00267-8.
2. Schoeler NE, Cross JH, Drury S, et al. Favourable
4. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond
response to ketogenic dietary therapies: undiagnosed glu-
weight loss: a review of the therapeutic uses of very-
cose 1 transporter deficiency syndrome is only one factor.
low-carbohydrate (ketogenic) diets. Eur J Clin Nutr
Dev Med Child Neurol 2015; 57: 969–76.
2013; 67: 789–96.
Pathways to good hand function after early brain injury ANNA P BASU Institute of Neuroscience, Newcastle University, Newcastle, UK. doi: 10.1111/dmcn.12836 This commentary is on the case report by Fiori et al. on pages 977–980 of this issue.
Fiori et al.1 describe a left-handed adolescent with mirror movements and a fast corticospinal tract projection from the right motor cortex, influencing hand muscles bilaterally. Despite imaging evidence of an early left-sided white matter lesion and small left caudate, the patient did not have hemiplegia. The case is surprising in view of research indicating that after unilateral brain injury, a fast ipsilateral corticospinal tract projection from the undamaged hemisphere is associated with a relatively poor motor outcome.2–4 This occurs through progressive activity-dependent displacement of the remaining contralateral corticospinal tract projections from the damaged hemisphere. Although those with ipsilateral corticospinal tract projections from lesions sustained earlier in brain development generally (but not always) fare better, normal motor outcome has not previously been reported. The case raises interesting questions. Firstly, what constitutes good hand function? The patient, who was perceived to have ‘good motor control’, presented with mirror movements. These are involuntary contralateral, predominantly distal upper limb movements, occurring simultaneously with and ‘mirroring’ the voluntary movement. They can be attributed to bilateral or branched corticospinal tract projections or in some cases (such as physiological mirror movements during childhood) to insufficient callosal inhibition or poor motor planning.5 They can occur in unilateral spastic cerebral palsy, in certain syndromes (Kallmann syndrome, Klippel–Feil syndrome, etc.), or in isolation, sometimes with identified genetic causes such as DCC mutations. They are problematic, interfere with performance of asymmetrical bimanual tasks, and can lead to discomfort. Management is centred around developing appropriate strategies for activities of
daily living as there is currently no effective treatment, although neurophysiological approaches modulating interhemispheric inhibition are under exploration for certain forms of mirror movements. Pragmatically, the lack of demonstration of motor control problems in this patient indicates a general need for better clinical assessments of bimanual dexterity. Secondly, what forms of post-lesional motor system reorganization are compatible with a good motor outcome? In this patient the symmetry demonstrated at the level of the pons and the residual corticospinal tract projection suggest that all descending motor pathways were at least partially preserved. This likely includes contralateral corticospinal tract projections from the damaged hemisphere to muscles other than those tested in the study and accounts for the relatively good outcome. The authors suggest that damage to descending pathways other than the corticospinal tract contributes to the motor impairments in congenital hemiplegia. This is an interesting viewpoint: most articles consider the role of these pathways in recovery. The reticulospinal and vestibulospinal tracts, and propriospinal system are under active investigation in motor recovery after stroke6 but have been less well considered after early brain injury, when the corticospinal tract remains the main focus. There are major differences between the developing and established motor systems. The fast ipsilateral corticospinal tract projections sometimes seen from the contralesional hemisphere after early unilateral brain injury do not arise after stroke in adults. These fast ipsilateral corticospinal tract projections can clearly cause motor control problems through mirror movements and displacement of more functional contralateral projections, but might still have some functional role. In contrast there is no evidence that the ipsilateral corticospinal tract contributes to motor recovery after stroke in adults.6 Additionally, although the human rubrospinal tract is vestigial, it may play a more active role in early motor system development and therefore also in recovery after early brain injury.3 We need to investigate post-lesional changes in the reticulospinal, vestibulospinal, and propriospinal pathways in the context Commentaries
897
