Changing faces of mitochondrial disease: autosomal recessive POLG disease mimicking myasthenia gravis and progressive supranuclear palsy.

Background: Mitochondrial disorders are known to cause diverse neurological phenotypes which cause a diagnostic challenge to most neurologists. Pathogenic polymerase gamma (POLG) variants have been described as a cause of chronic progressive external ophthalmoplegia, which manifests with ptosis, horizontal and vertical eye movement restriction and myopathy. Autosomal dominant progressive external ophthalmoplegia is rarely associated with Parkinsonism responsive to levodopa. Methods: We report a case of a 58-year-old man who presented with an eye movement disorder then Parkinsonism who made his way through the myasthenia then the movement disorder clinic. Results: A diagnostic right tibialis anterior biopsy revealed classical hallmarks of mitochondrial disease, and genetic testing identified compound heterozygous pathogenic gene variants in the POLG gene. The patient was diagnosed with autosomal recessive POLG disease. Conclusions: It is important to maintain a high index of suspicion of pathogenic POLG variants in patients presenting with atypical Parkinsonism and ophthalmoplegia. Patients with POLG-related disease will usually have ptosis, and downgaze is typically preserved until late in the disease. Accurate diagnosis is essential for appropriate prognosis and genetic counselling.

Late-onset cluster seizures and intellectual disability associated with a novel truncation variant in SMC1A.

SMC1A variants are known to cause Cornelia de Lange Syndrome (CdLS) which encompasses a clinical spectrum of intellectual disability, dysmorphic features (long or thick eyebrows, a hypomorphic philtrum and small nose) and, in some cases, epilepsy. More recently, SMC1A truncating variants have been described as the cause of a neurodevelopmental disorder with early-childhood onset drug-resistant epilepsy with seizures that occur in clusters, similar to that seen in PCDH19-related epilepsy, but without the classical features of CdLS. Here, we report the case of a 28-year-old woman with a de novo heterozygous truncating variant in SMC1A who unusually presented with seizures at the late age of 12 years and had normal development into adulthood.

A review of the clinical spectrum of BRAT1 disorders and case of developmental and epileptic encephalopathy surviving into adulthood.

Pathogenic variants in BRAT1 are associated with a spectrum of clinical syndromes ranging from Lethal Neonatal Rigidity and Multifocal Seizure syndrome (RMFSL) to Neurodevelopmental Disorder with Cerebellar Atrophy and with or without Seizures (NEDCAS). RMFSL is characterized by early-onset multifocal seizures with microcephaly. Death occurs during infancy although a less severe course with later onset seizures and longer survival into childhood has been described. Here, we summarize published cases of BRAT1 disorders and present the case of a 20-year-old man with two heterozygous BRAT1 variants and a relatively later age of seizure onset with survival into adulthood. This case expands the spectrum of disease associated with BRAT1 variants and highlights the utility of genetic testing to identify the cause of developmental and epileptic encephalopathies where clinical heterogeneity within a spectrum of disease exists.