Twenty patients with myopathic mitochondrial DNA (mtDNA) depletion syndrome (MDS) were screened for mutations in thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) genes at Columbia University, New York, NY. Four patients from two families had TK2 mutations, and none had dGK mutations. Two siblings were compound heterozygous for a H90N and a T77M mutation. Other siblings had a homozygous I22M mutation, one having spinal muscular atrophy (SMA) and lower motor neuron disease. Muscle TK2 activity was reduced compared to controls (28% cf 37%). All 20 patients had COX-negative fibers on muscle biopsies.

In Family I, Patient 1, a Hispanic boy, had nonconsanguinous parents. Normal until 12 months of age, he developed a progressive ataxic gait impairment, and was unable to walk or stand by 2 years. Muscle weakness and hypotonia involved shoulder and hip girdle muscles, respiratory insufficiency necessitating mechanical ventilation was present by 3 years of age, and he died at 40 months. Laboratory studies had shown an elevated CK level (1.238 U/L, n<200), and nonspecific organic aciduria. An older sister (patient 2) had a slower course, falling frequently at age 16 months, and was unable to walk by 4 years of age. Her CK was 950 U/L and she had lactic acidosis (12 mmol/L. n<2.2). A younger sister was asymptomatic. In Family 2, Patient 4 lost his ability to walk by 2 years, and had severe proximal weakness, muscle wasting, areflexia, and scoliosis at age 3 years. His cognitive function and language were normal for his age. EMG showed chronic partial denervation, fibrillations, and loss of motor unit potentials, compatible with SMA. Serum CK and lactate were mildly increased. He is alive at 48 months of age. His sister, who presented with weakness and hypotonia in early infancy, episodic vomiting, failure to thrive, and metabolic acidosis, had a primary myopathy. She died at 2 years of age, with respiratory infection and insufficiency. The clinical expression of TK2 mutations may be myopathic or neuropathic and the myopathic form is genetically heterogeneous. [1]

COMMENT. Mitochondrial DNA depletion syndrome (MDS) is an autosomal recessive disorder of early childhood that involves muscle (myopathic form) or liver and brain (hepatocerebral form). The myopathic form is characterized by progressive weakness, hypotonia, areflexia, and respiratory failure before 10 years of age. MDS is a heterogeneous disorder in which mtDNA depletion in affected tissues is generally proportional to the severity of symptoms. Mutations in the thymidine kinase gene (TK2), involved in deoxyribonucleotide metasbolism, can be manifested clinically by a pure myopathy or spinal muscular atrophy. Other genes may also be involved in the etiology of myopathic MDS.