Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (Fardeau et al., 1978; Selcen and Engel, 2003). A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see 613869. For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

A rare genetic autosomal recessive spastic ataxia disease with characteristics of the onset in early childhood of spastic paraparesis, cerebellar ataxia, dysarthria and optic atrophy. Caused by homozygous mutation in the MTPAP gene on chromosome 10p11.

A rare genetic principally axonal peripheral sensorimotor neuropathy with an X-linked dominant inheritance pattern and the childhood-onset of slowly progressive, moderate to severe, distal muscle weakness and atrophy of the lower extremities, as well as distal, pan modal sensory abnormalities, bilateral foot deformities (pes cavus, clawed toes), absent ankle reflexes and gait abnormalities (steppage gait). Females are usually asymptomatic or only present mild manifestations (mild postural hand tremor, mild wasting of hand intrinsic muscles).

Autosomal dominant distal hereditary motor neuronopathy-6 (HMND6) is a neurologic disorder characterized by onset of slowly progressive distal lower limb weakness and atrophy between the second and fourth decades of life. Weakness usually begins in the calf muscles and later involves more proximal muscles. The severity is variable, and some patients have difficulty walking or running. Most also have upper limb involvement, particularly of the triceps and intrinsic hand muscles. Some patients may lose independent ambulation later in the disease course. Sensory impairment is typically not present, and cognition and bulbar function are normal (summary by Sumner et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant distal HMN (dHMN), see HMND1 (182960).

Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT). MMD (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes in this spectrum are scapuloperoneal syndrome and congenital muscular dystrophy. Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only. DMAT is characterized by early and predominant distal muscle weakness, particularly of the muscles of the anterior compartment of the legs.

SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013). For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).