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Bcl-2-associated athanogene 3 (BAG3) myopathy is a rare myofibrillar myopathy characterized by toe walking and clumsiness in the first decade with rapid progression to cardiomyopathy and restrictive lung disease in the second decade. Most patients (18 patients) have the c.626C >T (p.Pro209Leu) mutation. We describe BAG3 myopathy due to p.Pro209Leu in a 13-year-old girl with initial prominent neuropathic phenotype and no cardiac or respiratory involvement. Parents reported toe walking and clumsiness since 3 years old. Examination at the age of 13 years showed findings suggestive of Charcot-Marie-Tooth disease. Nerve conduction studies revealed demyelinating polyneuropathy. Next-generation sequencing panel for inherited neuropathies was unrevealing. Whole exome sequencing identified a de novo mutation in BAG3. Muscle biopsy confirmed myofibrillar myopathy. No cardiac involvement or symptoms of respiratory involvement at the age of 14 years. This case emphasizes the phenotypic variability of BAG3 myopathy and the importance of thorough electrophysiological examination and muscle pathology for establishing a precise diagnosis.

A 74-year-old man with no relevant medical history presented with 5 years of slowly progressive bilateral foot drop. He had used ankle foot orthoses for 3 years prior to presentation. There was no report of upper extremity weakness, numbness, paresthesia, myalgias, muscle cramps, or stiffness. He had attained age-appropriate developmental milestones as a child and was athletic, keeping up with his peers. His mother had bilateral foot drop, ankle contractures, and difficulty with ambulation. His brother, 2 daughters, and a son lacked similar symptoms. Neurologic examination showed bilateral distal lower extremity weakness (Medical Research Council grade 0/5 ankle dorsiflexion and eversion and grade 4/5 ankle plantar flexion and inversion), symmetric distal leg and intrinsic foot muscle wasting, absent patellar and Achilles tendon reflexes, and a steppage gait. Tone was reduced at bilateral ankles. Sensory examination including light touch, pinprick, vibration, and proprioception was intact. Mild bilateral pes cavus and hammertoes were noted. The remainder of the neurologic and physical examination was normal.

A 6-year-old biracial (Black and White) boy presented with worsening muscle twitching and stiffness. He had normal birth and development. His family noticed muscle twitching involving his thighs when he was 3 years old. Over the next 3 years, twitching spread to involve shoulders, chest, lower back, arms, and lower legs. The patient would feel muscle twitching underneath his skin and at times, these could be visible. His symptoms were worse with cold exposure. Recently, he started experiencing difficulties with fine motor activities such as writing, holding pencils, tying shoelaces, and buttoning. The patient denied myalgia, weakness, rhabdomyolysis, and paresthesias. Medical history includes well-controlled asthma, allergic rhinitis, right hydrocelectomy, and a small bowel intussusception. Family history was unremarkable. Neurologic examination revealed increased appendicular muscle tone, fasciculations involving upper and lower extremities, anterior chest, and paraspinal muscles, mild difficulty releasing hand grip, nasal dysarthria, and bilateral tight heel cords. Sensory examination, reflexes, and gait including heel and toe walking were normal.

A 39-year-old man of Ecuadorian descent presented with a history of seizures, visual impairment, and ataxia. He had a normal birth and early developmental history. His first seizure was a generalized tonic-clonic seizure (GTCS) at 16 years old. Around the same time, he also started experiencing 1–2 myoclonic jerks per day. The myoclonic jerks progressively worsened over a period of 20 years to 15–20 episodes per day. GTCS continued to occur 1–2 times a year until the age of 24 years. EEG revealed multiple brief myoclonic seizures and generalized slow spike/polyspike wave complexes consistent with primary generalized epilepsy. Despite valproic acid, zonisamide, and clonazepam, his seizure control remained poor. When he was 30 years old, he began to have blurring of his vision; ophthalmologic evaluation at that time revealed bilateral cherry-red spots. Optical coherence tomography showed hyperreflectivity in the superficial layers of the retina at the posterior pole consistent with abnormal storage in the ganglion cells. An electroretinogram showed normal rod and cone responses. Flash visual evoked responses demonstrated a delay in the P100 response consistent with dysfunction of the visual pathways. His medical and family history was otherwise noncontributory. Gross physical examination was within normal limits. Neurologic examination demonstrated severe myoclonus of the face interrupting his speech, frequent myoclonus of the arms, truncal and appendicular ataxia, and broad-based ataxic gait. MRI of the brain with and without gadolinium was normal. Chromosome single nucleotide polymorphism microarray revealed long contiguous regions of allele homozygosity (>10 MB) in multiple chromosomes. A query of the regions of homozygosity that was subsequently narrowed down using his clinical presentation identified NEU1 as a candidate gene. Sequencing of NEU1 revealed a homozygous missense mutation c.629C>T (p.Pro210Leu). Enzymatic testing in fibroblasts showed sialidase activity to be deficient (0 nmol/h/mg; ref: 23–74). β-Galactosidase activity was within normal limits.

Leigh syndrome is clinically and genetically heterogeneous, associated with mutations in mitochondrial and nuclear genes.(1) Diagnostic criteria include progressive disorder with motor and intellectual delay/regression; signs and symptoms of brainstem and/or basal ganglia disease; raised lactate concentration in blood and/or CSF; and one or more of the following: (1) characteristic features on neuroimaging (bilateral symmetrical hyperintensities in brainstem, basal ganglia, dentate nuclei, and optic nerves on T2-weighted MRI); (2) typical neuropathologic changes; and (3) typical neuropathology in a similarly affected sibling.(2) We describe 2 African American siblings who have a mutation in the mitochondrial MT-TL2 gene and a clinical diagnosis of Leigh syndrome. The same mutation is also identified in their neurologically asymptomatic mother.