The proband, a 20-year-old male, was referred to the Neurometabolic Clinic at McMaster University for investigation in the context of gross developmental delay, emotional outbursts, speech and swallowing difficulties, hypotonia, and ataxia since childhood. He was born at term following an uncomplicated pregnancy (birth weight 3,200 g) and developed appropriately until 8 months of age, where he had developmental regression following a mild traumatic brain injury. Axial hypotonia was noted at 1 year of age. He had delays in his walking, started to cruise at 3 years of age and was non-verbal. During his early adulthood, his symptoms progressed, with severe generalized slowing of movements, muscular fatigue, and swallowing difficulties. Currently, he spends most of his time in his wheelchair but walks on occasion with one person assistance. There were no ocular, dental, auricular, or skeletal anomalies identified by clinical examination and targeted X-ray evaluation. His parents are double first cousins from Pakistan with an unremarkable medical or family history. The other family members do not report a history of developmental delay or neurological features.
The proband's physical examination was abnormal. He appeared short and cachectic; he was 50.5 kg, 161.5 cm tall and used a wheelchair for ambulation. He was unable to sit independently. There was evidence of cognitive impairment and non-verbal vocalization, including screams. He would occasionally swat at the examiner. Cranial nerve examination demonstrated horizontal and rotatory nystagmus without ptosis, cataracts, or retinopathy. He had a right eye esotropia. Cerebellar examination demonstrated ataxia and bilateral coarse hand tremors. Lower cranial nerves and hearing were normal. Motor examination demonstrated generally reduced muscle bulk, paratonia, with grade 3-4-/5 muscle weakness. He had normal muscle stretch reflexes in the upper extremities and absent in the lower extremities with downgoing toes. His serial brain MRI's demonstrated progressive cerebellar and vermian atrophy with increased FLAIR signal in cerebellum and periventricular white matter. His echocardiogram, nerve conduction study, POLG sequencing, serum lactate, and karyotype were normal.