Muscular Dystrophy, Congenital, With Cataracts And Intellectual Disability

A number sign (#) is used with this entry because of evidence that congenital muscular dystrophy with cataracts and intellectual disability (MDCCAID) is caused by homozygous or compound heterozygous mutation in the INPP5K gene (607875) on chromosome 17p13.

Description

MDCCAID is an autosomal recessive form of muscular dystrophy with onset of progressive muscle weakness in early childhood. Almost all patients also have early-onset cataracts, most have intellectual disability of varying severity, and some have seizures (summary by Wiessner et al., 2017 and Osborn et al., 2017).

Clinical Features

Wiessner et al. (2017) reported 12 patients from 8 unrelated families with congenital muscular dystrophy. The patients ranged in age from 6 to 37 years, and 5 of the families were consanguineous. Most patients presented with hypotonia at birth, although a few presented with global or motor developmental delay in the first years of life; 2 presented with early-onset cataracts. Features included delayed motor milestones, hypotonia with muscle weakness and atrophy affecting the proximal muscles more than the distal muscles, and the lower limbs more than the upper limbs, resulting in gait difficulties. The muscle weakness tended to stabilize for several years, but motor capabilities deteriorated, and most patients became wheelchair-bound in adulthood. Five patients developed respiratory compromise; none had cardiac involvement. Eight patients had mild cognitive deficits, but 4 had normal intelligence. More variable features found in some patients included contractures, scoliosis, spinal rigidity, hyperlaxity, and seizures. Laboratory studies showed increased serum creatine kinase, and muscle biopsies showed nonspecific dystrophic changes, such as increased fiber size variation, fibrosis, increased adipose tissue, and some internal nuclei. Three biopsies showed small vacuoles. Electron microscopy of 2 patient biopsies showed reduction of myofibrils and disrupted Z-lines. EMG studies in 3 patients were consistent with a myopathic process. Wiessner et al. (2017) noted the phenotypic similarities to Marinesco-Sjogren syndrome (MSS; 248800).

Osborn et al. (2017) reported 5 patients, including 2 sisters born of consanguineous Arab parents, with congenital muscular dystrophy. The patients showed delayed psychomotor development in infancy with difficulty walking due to proximal muscle weakness. Three patients were wheelchair-bound at ages 13, 21, and 31 years. Four patients showed spasticity of the lower limbs, with spastic gait, hyperreflexia, pyramidal signs, and toe walking. Three patients had cataracts, and 3 had strabismus. Additional features included muscle atrophy, short stature, hyperlordosis, Gowers sign, inability to climb stairs, and hypotonia and hyporeflexia of the upper limbs; 3 patients had seizures and 4 had microcephaly. Muscle biopsies showed fiber size variability, increased connective tissue, and atrophic fibers. Muscle biopsy in 2 unrelated patients showed decreased glycosylation of alpha-DAG (128239), reminiscent of dystroglycanopathies (see, e.g., MDDGC1, 609308). Laboratory studies showed increased serum creatine kinase.

Inheritance

The transmission pattern of MDCCAID in the families reported by Wiessner et al. (2017) and Osborn et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 12 patients from 8 unrelated families with MDCCAID, Wiessner et al. (2017) identified homozygous or compound heterozygous mutations in the INPP5K gene (see, e.g., 607875.0001 and 607875.0002). Patients from 6 families of Bangladeshi or Pakistani origin, 5 of which were consanguineous, carried the same homozygous missense mutation (I50T; 607875.0001). The mutations in the first family were found by a combination of linkage analysis and whole-exome sequencing. Mutations in 6 additional families were found by Sanger sequencing of the INPP5K gene in 12 families with the disorder; the mutations in the last family were found by Sanger sequencing of 21 isolated cases with a similar phenotype. In vitro studies showed that all the mutations resulted in a significant decrease in enzyme activity. Patient cells did not show evidence of the endoplasmic reticulum (ER) unfolded protein response or of increased autophagy in skeletal muscle, suggesting another pathogenic mechanism.

In 5 patients from 4 unrelated families with MDCCAID, Osborn et al. (2017) identified homozygous or compound heterozygous mutations in the INPP5K gene (607875.0003-607875.0007). The mutations were found by exome sequencing, and in vitro studies showed that all resulted in a significant decrease in enzyme activity.

Animal Model

Wiessner et al. (2017) found that morpholino knockdown of the inpp5k orthologs in zebrafish embryos resulted in curled and shortened tails, impaired swimming and touch-evoked escape responses, and smaller eyes compared to controls. Skeletal muscle morphology in mutant fish was also abnormal, including disruption of both slow- and fast-twitch fiber types.

Osborn et al. (2017) found that morpholino knockdown of inpp5k orthologs in zebrafish embryos resulted in microphthalmia, microcephaly, curved and shortened body, and reduced touch-evoked motility. Morphant eyes showed disorganized lens cortex with cell nuclei present in the center of the lens nucleus. Skeletal muscle fibers were disorganized and showed reduced synaptic formation at the neuromuscular junction. Electron microscopy of morphant skeletal muscle showed undefined A- and I-bands, shortened sarcomeres with smaller sarcomeric triads, and loose myofibrils.