Neuromuscular Disorders 31 (2021) S47-S162 paresis is common. We describe a male patient presenting clinically at 2 years of age with toe-walking. His subsequent course was characterized by progressive distal weakness and loss of ambulation. Electromyelogram and nerve conduction studies demonstrated axonal injury in both sensory and motor nerves, affecting lower greater than upper extremities. Invitae Comprehensive Neuropathies Panel identified a known pathogenic variant in GDAP1 , c.116delA (p.Lys39Argfs * 5) as well as a Variant of Uncertain Significance (VUS) in GDAP1 , c.393G > C (p.Leu131Phe). Familial testing confirmed that GDAP1 variants were inherited (one from each unaffected parent). The patient regained ambulation after bilateral tendon lengthenings (Achilles, posterior tibial and intramuscular flexor digitorum longus (FDL)) and tenotomies (toe flexor, distal flexor hallucis longus, FDL 2-5). At recent clinic visit (age 5 years), motor function continued to improve. His speech has been unaffected to date. This case of compound heterozygous variants in GDAP1 causing Charcot-Marie-Tooth Disease, supports reclassifying c.393G > C (p.Leu131Phe) from VUS to likely pathogenic. It also provides additional insights regarding the natural history of GDAP1 -related CMT.
Kennedy disease is a rare X-linked disorder caused by an expanded CAG repeat (CAG > 37) in the androgen receptor gene. The disorder mainly affects men, causing spinal and bulbar muscular atrophy. Female heterozygous carriers are usually asymptomatic. However, females with expansions on both alleles have rarely been reported. Here we present a 21-year follow-up of two sisters with biallelic CAG expansions in the androgen receptor gene. In a family with several affected males with Kennedy disease, two sisters inherited one CAG expansion from their mother who was a carrier, and one from their father who had Kennedy disease. Genetic testing revealed 38/38, and 38/40 CAG expansions in the youngest and oldest sister, respectively. Around fifty years of age, both sisters presented with similar symptoms with chronic back pain, pain and cramps in upper and lower extremities, as well as fasciculations in their faces and extremities. They were both diagnosed with hypertension, elevated HbA1c, cholesterol and liver enzyme levels and later developed osteoporosis. The neurological examination was normal except for postural hand tremor. EMG revealed chronic axonal neuropathy. Reevaluation of the patients at 74 years old and 83 years old showed that both had developed bulbar manifestations with weak voices and slight dysphagia. As opposed to male patients with Kennedy disease, these two females showed minimal disease progression, and have maintained normal level of function into old age. The obvious sex differences we found in Kennedy disease are not well understood. We speculate that these differences may be a result of different tissue distributions of the androgen receptors in women and men.
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