Severe Hypothyroidism Complicated by Myopathy and Neuropathy with Atypical Demyelinating Features

Autoimmune hypothyroidism may result in a wide range of neuromuscular disorders. The frequently observed neurological manifestations of acquired hypothyroidism include mild to moderate myopathy and sensorimotor neuropathy, which usually resolve by clinical and electrophysiological criteria, in adults treated with thyroid hormone replacement. We report a case of a 30-year-old male with severe hypothyroidism secondary to chronic autoimmune thyroiditis who presented with a 2-year history of progressive fatigue, upper and lower limb weakness, myalgia, and intermittent paraesthesia. His neurological exam demonstrated proximal and distal muscle weakness, lower limb areflexia, and relatively intact sensory modalities. The patient’s biochemistry revealed unusually and profoundly raised the thyroid stimulating hormone (TSH) level of 405.5 mIU/L (reference range (RR): 0.27–4.2 mIU/L) and creatine kinase (CK) level of 20,804 U/L (RR: 45–250 U/L), while his nerve conduction studies (NCS) demonstrated severe sensorimotor polyneuropathy with both axonal and demyelinating features. Thyroid hormone replacement therapy over the first 3 months resulted in biochemical normalization of his extremely deranged thyroid function tests (TFTs) and CK levels. At 12 months, despite maintaining euthyroidism and noticeable improvement in strength, his nerve conduction studies (NCS) demonstrated the continued absence of distal motor and sensory responses in his lower limbs with only partial improvement in sensory amplitudes and conduction velocities in his upper limbs. This report highlights the potential for severe neuromuscular consequences from advanced and chronic autoimmune hypothyroidism. The patient’s myopathy has resolved over a period of three months with prompt normalization of CK levels. Concerningly, the patient achieved significant but incomplete recovery from his mixed axonal and demyelinating neuropathy with residual mild distal weakness and areflexia in his lower limbs and persistent motor and sensory impairments on his NCS. The severity and incomplete resolution of our patient’s neurological manifestations emphasize the importance of early diagnosis and the need for prompt therapeutic intervention for hypothyroidism

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort