X-linked spinocerebellar ataxia-6 with or without sideroblastic anemia (SCAX6) is an X-linked recessive disorder characterized by delayed motor development apparent in infancy with delayed walking (often by several years) due to ataxia and poor coordination. Additional features may include dysmetria, dysarthria, spasticity of the lower limbs, hyperreflexia, dysdiadochokinesis, strabismus, and nystagmus. The disorder is slowly progressive, and patients often lose ambulation. Brain imaging usually shows cerebellar atrophy. Most affected individuals have mild hypochromic, microcytic sideroblastic anemia, which may be asymptomatic. Laboratory studies show increased free erythrocyte protoporphyrin (FEP) and ringed sideroblasts on bone marrow biopsy. Female carriers do not have neurologic abnormalities, but may have subtle findings on peripheral blood smear (Pagon et al., 1985; D'Hooghe et al., 2012). For a discussion of genetic heterogeneity of X-linked spinocerebellar ataxia (SCAX), see SCAX1 (302500).

Mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms at birth or in the first weeks or months of life. Affected individuals have severe hypotonia, often associated with feeding difficulties and respiratory insufficiency necessitating tube feeding and mechanical ventilation. The vast majority of patients develop hypertrophic cardiomyopathy in the first days or weeks of life, which usually leads to death in infancy or early childhood. Patients also show neurologic abnormalities, including developmental delay, nystagmus, fasciculations, dystonia, EEG changes, and brain imaging abnormalities compatible with a diagnosis of Leigh syndrome (see 256000). There may also be evidence of systemic involvement with hepatomegaly and myopathy, although neurogenic muscle atrophy is more common and may resemble spinal muscular atrophy type I (SMA1; 253300). Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure (summary by Papadopoulou et al., 1999). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.