OP10 – 2707: Childhood-onset ataxic gait solved by muscle biopsy

Abstract

Objective The differential diagnosis of childhood-onset ataxia may be challenging, especially in the absence of brain MRI or lab abnormalities. We present a case where the findings of intra-axonal spheroids on muscle biopsy led to the diagnosis of atypical neuraxonal dystrophy (NAD) due to a compound heterozygous mutation in PLA2G6. Methods and results The proband was referred for frequent falls at age 4 years. Acquisition of early developmental milestones was normal. Concerns were first expressed at age 3 years, when she developed an unsteady gait. On examination eye movements were slightly saccadic, gait ataxic, balance poor. She had mild proximal muscle weakness with positive sign of Gowers. Deep tendon reflexes were present. She was at times introverted and sometimes overfamiliar. Formal evaluation of development showed normal intelligence, normal speech and language development except for intermittent whispering, and confirmed poor coordination and balance. Visuo-spatial skills were normal. Brain MRI was normal and remained so after 3 years. EMG and nerve conduction studies, fundoscopy, lactate, alpha-foetoprotein and urinary catecholamines were normal. Friedreich ataxia and Pompe disease were excluded. Further concern about a possible myopathy led to muscle biopsy. Histological examination showed a predominance of type1 fibers. Extensive immunohistochemical testing was normal. Electron microscopy revealed intra-axonal spheroids in the peri- and endomysial myelinated nerve bundles as well as in the motor endplates. Neuroaxonal spheroids are present in >80% of cases with PLA2G6-associated neurodegeneration (PLAN) and is rarely seen in mitochondrial protein associated neurodegeneration (MPAN). Mutation analysis of PLA2G6 showed the compound heterozygous presence of the c.1021G>A (p.Ala341Thr) and c.2036G>T (p.Gly679Val) mutations in the patient, while both parents were heterozygous carriers, confirming the diagnosis of atypical NAD. Conclusion This report highlights that childhood-onset gait ataxia with subtle behavioral and/or expressive speech abnormalities may be the presenting features of atypical NAD. The differential diagnosis of childhood-onset ataxia may be challenging, especially in the absence of brain MRI or lab abnormalities. We present a case where the findings of intra-axonal spheroids on muscle biopsy led to the diagnosis of atypical neuraxonal dystrophy (NAD) due to a compound heterozygous mutation in PLA2G6. The proband was referred for frequent falls at age 4 years. Acquisition of early developmental milestones was normal. Concerns were first expressed at age 3 years, when she developed an unsteady gait. On examination eye movements were slightly saccadic, gait ataxic, balance poor. She had mild proximal muscle weakness with positive sign of Gowers. Deep tendon reflexes were present. She was at times introverted and sometimes overfamiliar. Formal evaluation of development showed normal intelligence, normal speech and language development except for intermittent whispering, and confirmed poor coordination and balance. Visuo-spatial skills were normal. Brain MRI was normal and remained so after 3 years. EMG and nerve conduction studies, fundoscopy, lactate, alpha-foetoprotein and urinary catecholamines were normal. Friedreich ataxia and Pompe disease were excluded. Further concern about a possible myopathy led to muscle biopsy. Histological examination showed a predominance of type1 fibers. Extensive immunohistochemical testing was normal. Electron microscopy revealed intra-axonal spheroids in the peri- and endomysial myelinated nerve bundles as well as in the motor endplates. Neuroaxonal spheroids are present in >80% of cases with PLA2G6-associated neurodegeneration (PLAN) and is rarely seen in mitochondrial protein associated neurodegeneration (MPAN). Mutation analysis of PLA2G6 showed the compound heterozygous presence of the c.1021G>A (p.Ala341Thr) and c.2036G>T (p.Gly679Val) mutations in the patient, while both parents were heterozygous carriers, confirming the diagnosis of atypical NAD. This report highlights that childhood-onset gait ataxia with subtle behavioral and/or expressive speech abnormalities may be the presenting features of atypical NAD.