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Child Neurology: Hereditary Spastic Paraplegia in Children S.T RESIDENT & FELLOW SECTION Child Neurology: Section Editor Hereditary spastic paraplegia in children Mitchell S.V. Elkind, MD, MS S.T. de Bot, MD Because the medical literature on hereditary spastic clinical feature is progressive lower limb spasticity B.P.C. van de paraplegia (HSP) is dominated by descriptions of secondary to pyramidal tract dysfunction. HSP is Warrenburg, MD, adult case series, there is less emphasis on the genetic classified as pure if neurologic signs are limited to the PhD evaluation in suspected pediatric cases of HSP. The lower limbs (although urinary urgency and mild im- H.P.H. Kremer, differential diagnosis of progressive spastic paraplegia pairment of vibration perception in the distal lower MD, PhD strongly depends on the age at onset, as well as the ac- extremities may occur). In contrast, complicated M.A.A.P. Willemsen, companying clinical features, possible abnormalities on forms of HSP display additional neurologic and MRI abnormalities such as ataxia, more significant periph- MD, PhD MRI, and family history. In order to develop a rational eral neuropathy, mental retardation, or a thin corpus diagnostic strategy for pediatric HSP cases, we per- callosum. HSP may be inherited as an autosomal formed a literature search focusing on presenting signs Address correspondence and dominant, autosomal recessive, or X-linked disease. reprint requests to Dr. S.T. de and symptoms, age at onset, and genotype. We present Over 40 loci and nearly 20 genes have already been Bot, Radboud University a case of a young boy with a REEP1 (SPG31) mutation. Nijmegen Medical Centre, identified.1 Autosomal dominant transmission is ob- Department of Neurology, PO served in 70% to 80% of all cases and typically re- Box 9101, 6500 HB, Nijmegen, CASE REPORT A 4-year-old boy presented with 2 the Netherlands progressive walking difficulties from the time he sults in pure HSP. [email protected] started walking at the age of 12 to 13 months. His Spastic paraplegia is a common problem in the daily family history was significant for minimal gait abnor- practice of pediatric neurologists, generally caused by malities with onset after age 35, occurring in the pa- acquired brain disorders such as perinatal asphyxia or tient’s mother, maternal grandfather, and maternal infections early in life resulting in cerebral palsy. In ad- aunt; none of them had ever sought medical atten- dition, there is a long list of more rare disorders to con- tion. Neurologic examination revealed a mildly spas- sider when confronted with spastic paraplegia including tic gait and marked lower limb hyperreflexia with structural, infectious, demyelinating, and metabolic dis- 3 bilateral Babinski signs present. Vibration perception orders (table). Only in a small minority of cases does was reduced at the ankles. Neurologic examination of HSP underlie the spastic syndrome. Many patients with the patient’s mother and maternal aunt revealed subtle childhood-onset HSP are mistakenly diagnosed with 4,5 gait abnormalities with bilateral Babinski signs present. cerebral palsy. In children with spastic paraplegia in MRI of the brain and spinal cord and general whom no acquired cause can be identified, HSP should metabolic screening revealed no abnormalities. Diag- be considered. A positive family history aids with the nostic genetic testing in both the patient and his diagnosis. Our case illustrates the importance of neuro- mother revealed a pathogenic mutation (c.417 ϩ 1 logic examination of family members who may be GϾT) in REEP1 (SPG31) which causes a pure HSP. mildly affected. Mutations in ATL1 (SPG3A) and SPAST (SPG4) Since the medical literature on HSP is dominated had previously been excluded. by adult case series, it is difficult to decide how the genetic evaluation should be structured when a child DISCUSSION HSP is a genetically and clinically is suspected to have HSP. In order to develop a ratio- heterogeneous group of disorders in which the main nal diagnostic strategy for HSP in children, we per- GLOSSARY ATL1 ϭ atlastin (GTPase) 1; BSCL2 ϭ Berardinelli-Seip congenital lipodystrophy 2 (seipin); KIF5A ϭ kinesin family member 5A; L1CAM ϭ L1 cell adhesion molecule; NIPA1 ϭ nonimprinted in Prader-Willi/Angelman syndrome region protein 1; PLP1 ϭ proteolipid protein 1; REEP1 ϭ receptor expression-enhancing protein 1; SPAST ϭ spastin; SPG ϭ spastic paraplegia gene; ZFYVE26 ϭ zinc finger FYVE domain-containing protein 26 (spastizin). From the Departments of Neurology (S.T.d.B., B.P.C.v.d.W.) and Paediatric Neurology (M.A.A.P.W.), Donders Centre for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen; and Department Of Neurology (H.P.H.K.), University Medical Centre Groningen, Groningen, the Netherlands. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2010 by AAN Enterprises, Inc. e75 Table Differential diagnosis of spastic paraplegia Differential diagnosis of spastic paraplegia with additional Abnormalities on MRI abnormalities on MRI of the brain HSPs Leukoencephalopathy Many neurometabolic and other hereditary white matter disorders SPG4 (some), SPG11, with characteristic MRI pattern, like Krabbe disease, Alexander SPG15, SPG21 disease, X-linked adrenoleukodystrophy, vanishing white matter; inflammatory disorders like multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica Thin corpus callosum Thin corpus callosum ϩ epilepsy, Andermann syndrome SPG1, SPG4 (some), SPG11, SPG15, SPG21, SPG32, Cerebellar atrophy See cerebellar ataxia (below) SPG7 Differential diagnosis of spastic paraplegia with additional Additional clinical features clinical features HSPs Mental retardation Many neurometabolic or neurogenetic disorders; sometimes SPG1, SPG2, SPG11, recognizable based on MRI abnormalities (see top of table) or SPG14, SPG15, further additional features (see below) SPG16, SPG20, SPG21, SPG23, SPG27, SPG32, SPG35 Dysmorphisms Andermann syndrome, hydrocephalus due to congenital stenosis SPG1, SPG23 of aqueduct of Sylvius Optic atrophy Cobalamin C disease, biotinidase deficiency, cerebral folate SPG7 deficiency, SPOAN, ARSACS, type III 3-methylglutaconic aciduria Retinopathy Cobalamin C disease, Sjögren-Larsson syndrome, SPG15 homocarnosinosis, abetalipoproteinemia Cataract Cerebrotendinous xanthomatosis, ␣-methyl-CoA racemase SPG9 deficiency Hearing loss/deafness Biotinidase deficiency, cerebral folate deficiency SPG29 Neuropathy/amyotrophy dHMN, HMSN V, cerebrotendinous xanthomatosis, cobalamin C SPG7, SPG9, SPG10, disease, MTHFR deficiency, metachromatic leukodystrophy, SPG11, SPG14, Krabbe disease, adrenomyeloneuropathy, polyglucosan body SPG17, SPG20, disease, ␣-methyl-CoA racemase deficiency, biotinidase SPG27, SPG38, deficiency, abetalipoproteinemia (posterior column), homocysteine SPG39 remethylation defects, SPOAN, ARSACS, Andermann syndrome Cerebellar ataxia Atypical Friedreich ataxia, cerebrotendinous xanthomatosis, triple SPG7, SPG15, H syndrome, cerebral folate deficiency, metachromatic SPG20, SPG21, leukodystrophy, SAX1, SAX2, ARSACS, ARSAL, Type III 3- SPG27 methylglutaconic aciduria, Alexander disease Extrapyramidal signs/diurnal Dopamine synthesis defects and cerebral folate deficiency SPG21, SPG23 fluctuations (dystonia), amyotrophic dystonic paraplegia (dystonia), (tremor) polyglucosan body disease, phenylketonuria and cerebrotendinous xanthomatosis (parkinsonism), dopa-responsive dystonia (diurnal fluctuations) Epilepsy Dopamine synthesis defects, ␣-methyl-CoA racemase deficiency, SPG2, SPG35 triple H syndrome, metachromatic leukodystrophy, cerebrotendinous xanthomatosis, arginase deficiency, cerebral folate deficiency, thin corpus callosum ϩ epilepsy, Alexander disease Cutaneous signs Cerebrotendinous xanthomatosis (xanthomas), biotinidase SPG23 (pigmentary deficiency (alopecia, dermatitis), Sjögren-Larsson (ichthyosis), abnormalities) adrenoleukodystrophy/adrenomyeloneuropathy (melanoderma) Episodes of confusion, nausea/ Cobalamin C disease, MTHFR deficiency, triple H, arginase SPG9 vomiting, or diarrhea deficiency, cerebrotendinous xanthomatosis (chronic diarrhea), (gastroesophageal adrenal insufficiency (adrenomyeloneuropathy, reflux), SPG29 adrenoleukodystrophy), abetalipoproteinemia (diarrhea), (hiatus hernia, homocysteine remethylation defects (confusion) hyperbilirubinemia) Abbreviations: ARSACS ϭ autosomal recessive spastic ataxia of Charlevoix-Saguenay; ARSAL ϭ autosomal recessive spastic ataxia with leukoencephalopathy; dHMN ϭ distal hereditary motor neuropathy; HMSN ϭ hereditary motor and sensory neuropathy; HSP ϭ hereditary spastic paraplegia; MTHFR ϭ 5,10-methylenetetrahydrofolate deficiency; SAX1/ SAX2 ϭ spastic ataxia; SPG1 ϭ L1CAM; SPG2 ϭ PLP1; SPG4 ϭ SPAST; SPG10 ϭ KIF5A; SPG15 ϭ ZFYVE26; SPG17 ϭ BSCL2; SPOAN ϭ spastic paraplegia, optic atrophy, and neuropathy; triple H syndrome ϭ hyperornithinemia- hyperammonemia-homocitrullinuria syndrome. formed a literature search focusing on presenting signs Characteristics. In the medical literature, symptom and symptoms, age at symptom onset, and genotype. We onset before age 18 has been documented in many also share some of our personal experiences from a clinic- HSP cases, particularly in the complicated forms, genetic database, as our institution has served as a tertiary which show a clear overlap with many metabolic referral center for Dutch HSP patients for over 2 decades. disorders and leukodystrophies. In a series of 23 e76 Neurology 75 November 9, 2010 children with HSP, 15 of 23 (65%)
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