Microcephaly 15, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-15 (MCPH15) is caused by homozygous mutation in the MFSD2A gene (614397) on chromosome 1p34.

For a phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Clinical Features

Guemez-Gamboa et al. (2015) reported 4 children from 2 unrelated consanguineous families of Libyan and Egyptian origin, respectively, with a lethal microcephalic disorder. The patients had progressive microcephaly (up to -6.2 SD), profoundly delayed psychomotor development with lack of head control, lack of ambulation, and lack of speech development. Additional neurologic features included spastic quadriparesis, hyperreflexia, hypotonia, and early-onset seizures. Brain imaging showed enlarged ventricles and hypoplasia of the corpus callosum, brainstem, and cerebellum. All the patients died before age 6 years. Laboratory studies showed that the patients had increased plasma lysophosphatidylcholine (LPC) levels compared to their parents and to controls.

Clinical Variability

Alakbarzade et al. (2015) reported a large consanguineous Pakistani kindred in which 10 individuals had microcephaly (greater than -3 SD), severe intellectual disability with absent speech, and spastic quadriparesis. Brain imaging of 2 patients showed a paucity of cerebral white matter, particularly posteriorly around the lateral ventricles. Myelination appeared complete, and cortical thickening and folding appeared normal.

Inheritance

The transmission pattern of MCPH15 in the families reported by Guemez-Gamboa et al. (2015) and Alakbarzade et al. (2015) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis of a large consanguineous Pakistani kindred with MCPH15, Alakbarzade et al. (2015) found significant linkage to a 19.9-Mb region on chromosome 1p34 (maximum lod score of 7.3).

Molecular Genetics

In affected members of 2 consanguineous families from northern Africa with MCPH15, Guemez-Gamboa et al. (2015) identified 2 different homozygous missense mutations in the MFSD2A gene (T159M, 614397.0001 and S166L, 614397.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the families. In vitro functional expression assays showed that the mutations resulted in complete loss of transport activity.

In affected members of a large consanguineous Pakistani kindred with MCPH15, Alakbarzade et al. (2015) identified a homozygous missense mutation in the MFSD2A gene (S339L; 614397.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression assays showed that the mutation resulted in a partial loss of transport function, which may have mitigated the phenotype compared to that observed in the patients reported by Guemez-Gamboa et al. (2015). Transport of LPC-docosahexaenoic acid (DHA) and LPC-oleate was significantly reduced, and transport of LPC-palmitate was almost abolished. Plasma levels of total LPC in homozygous carriers were increased by about 54% compared to controls, consistent with defective transport and uptake of LPC at the blood-brain barrier. The results showed that high-affinity MFSD2A ligands with unsaturated acyl chains were more significantly affected than low-affinity ligands with saturated fatty acyl chains. These findings suggested that mono- and polyunsaturated fatty acyl chains are the major plasma LPC species required for human brain growth.

Animal Model

Nguyen et al. (2014) found that Mfsd2a-deficient mice had markedly reduced levels of DHA in brain accompanied by neuronal cell loss in hippocampus and cerebellum, as well as cognitive deficits, severe anxiety, and microcephaly. Mfsd2a-deficient mice also had markedly reduced uptake of labeled LPC-DHA and other LPCs from plasma into brain, demonstrating that MFSD2A is required for brain uptake of DHA.

Guemez-Gamboa et al. (2015) found that morpholino knockdown of the orthologous mfsd2aa gene in zebrafish resulted in early postnatal lethality and microcephaly. Morphant zebrafish also showed disruption of the blood-brain barrier, manifest as extravasation of labeled dextrose, and this defect could be rescued by expression of wildtype mfsd2aa. Guemez-Gamboa et al. (2015) also found that Mfsd2a-null mice had an approximately 40% increase in plasma levels of LPC compared to controls, consistent with impaired uptake of LPC into the brain via Mfsd2a.