Because the medical literature on hereditary spastic paraplegia (HSP) is dominated by descriptions of adult case series, there is less emphasis on the genetic evaluation in suspected pediatric cases of HSP. The differential diagnosis of progressive spastic paraplegia strongly depends on the age at onset, as well as the accompanying clinical features, possible abnormalities on MRI, and family history. In order to develop a rational diagnostic strategy for pediatric HSP cases, we performed a literature search focusing on presenting signs and symptoms, age at onset, and genotype. We present a case of a young boy with a REEP1 (SPG31) mutation.
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A 4-year-old boy presented with progressive walking difficulties from the time he started walking at the age of 12 to 13 months. His family history was significant for minimal gait abnormalities with onset after age 35, occurring in the patient’s mother, maternal grandfather, and maternal aunt; none of them had ever sought medical attention. Neurologic examination revealed a mildly spastic gait and marked lower limb hyperreflexia with bilateral Babinski signs present. Vibration perception was reduced at the ankles. Neurologic examination of the patient’s mother and maternal aunt revealed subtle gait abnormalities with bilateral Babinski signs present.
MRI of the brain and spinal cord and general metabolic screening revealed no abnormalities. Diagnostic genetic testing in both the patient and his mother revealed a pathogenic mutation (c.417 + 1 G>T) in REEP1 (SPG31) which causes a pure HSP. Mutations in ATL1 (SPG3A) and SPAST (SPG4) had previously been excluded.
HSP is a genetically and clinically heterogeneous group of disorders in which the main clinical feature is progressive lower limb spasticity secondary to pyramidal tract dysfunction. HSP is classified as pure if neurologic signs are limited to the lower limbs (although urinary urgency and mild impairment of vibration perception in the distal lower extremities may occur). In contrast, complicated forms of HSP display additional neurologic and MRI abnormalities such as ataxia, more significant peripheral neuropathy, cognitive impairment, or a thin corpus callosum. HSP may be inherited as an autosomal dominant, autosomal recessive, or X-linked disease. Over 40 loci and nearly 20 genes have already been identified. Autosomal dominant transmission is observed in 70% to 80% of all cases and typically results in pure HSP.
Spastic paraplegia is a common problem in the daily practice of pediatric neurologists, generally caused by acquired brain disorders such as perinatal asphyxia or infections early in life resulting in cerebral palsy. In addition, there is a long list of more rare disorders to consider when confronted with spastic paraplegia including structural, infectious, demyelinating, and metabolic disorders. Only in a small minority of cases does HSP underlie the spastic syndrome. Many patients with childhood-onset HSP are mistakenly diagnosed with cerebral palsy. In children with spastic paraplegia in whom no acquired cause can be identified, HSP should be considered. A positive family history aids with the diagnosis. Our case illustrates the importance of neurologic examination of family members who may be mildly affected.
Since the medical literature on HSP is dominated by adult case series, it is difficult to decide how the genetic evaluation should be structured when a child is suspected to have HSP. In order to develop a rational diagnostic strategy for HSP in children, we performed a literature search focusing on presenting signs and symptoms, age at symptom onset, and genotype. We also share some of our personal experiences from a clinic-genetic database, as our institution has served as a tertiary referral center for Dutch HSP patients for over 2 decades.
In the medical literature, symptom onset before age 18 has been documented in many HSP cases, particularly in the complicated forms, which show a clear overlap with many metabolic disorders and leukodystrophies. In a series of 23 children with HSP, 15 of 23 (65%) were reported to have a complicated (mostly recessively inherited) HSP, compared to 8 of 23 (35%) with a pure HSP.
In our HSP database, an early age at symptom onset (prior to age 18) was found in 72 of 175 (41%) patients, with a heterogeneous genetic background; 47 of 72 (65%) autosomal dominant cases; 12 of 72 (17%) autosomal recessive cases; and 13 of 72 (18%) sporadic cases. Gait difficulties were the presenting symptom in 81%, with a mean age of 8 years. A complicated phenotype was present in 25%. Of these 72 early-onset HSP patients, at least 20 (28%) had presented in childhood to a pediatrician or pediatric neurologist.
Prior reviews have provided in-depth descriptions and overviews of all known HSP forms. In this article, we focus on the most prevalent (>5 families described) forms of HSP with a possible childhood onset.
SOURCE: Neurology. November 9, 2010 vol. 75 no. 19 e75-e79
Child Neurology: Hereditary spastic paraplegia in children
S.T. de Bot, MD, B.P.C. van de Warrenburg, MD, PhD, H.P.H. Kremer, MD, PhD and M.A.A.P. Willemsen, MD, PhD.
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 Nijmegan Medical Centre, Nijmegen; and Department of Neurology (H.P.H.K.), University Medical Centre Groningen, Groningen, the Netherlands.