Poretti-Boltshauser Syndrome

A number sign (#) is used with this entry because Poretti-Boltshauser syndrome (PTBHS) is caused by homozygous or compound heterozygous mutation in the LAMA1 gene (150320) on chromosome 18p11.

Description

Poretti-Boltshauser syndrome is an autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis hypoplasia, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. Affected individuals have delayed motor development and often have speech delay. Cognitive function can range from normal to intellectually disabled (summary by Aldinger et al., 2014).

Clinical Features

Poretti et al. (2014) retrospectively analyzed the clinical features of 7 children from 5 unrelated families who were found to have cerebellar cysts on brain imaging. The most prominent features included cerebellar ataxia, intellectual disability, and delayed language development. Five patients had oculomotor apraxia and 3 had severe myopia. Three patients had mildly elevated serum creatine kinase, but none had muscle weakness. Review of brain imaging showed cortical-subcortical cerebellar cysts and cerebellar dysplasia.

Aldinger et al. (2014) reported 7 patients from 5 unrelated families with a phenotype reminiscent of that described by Poretti et al. (2014). Three unrelated children, all with delayed motor development and 2 with speech delay, were found to have cerebellar dysplasia with cerebellar cysts on brain imaging. The children ranged in age from 25 to 36 months. Four patients from 2 families with a similar disorder were subsequently identified: 1 family contained 2 sisters aged 4.5 and 5.5 years, and the other contained a sister and brother aged 29 and 23 years. These 4 patients also had a history of motor delay, and 3 had speech delay. The sibs in their twenties had normal IQ; 1 had Asperger syndrome. All 7 patients had eye movement abnormalities, including strabismus, oculomotor apraxia, amblyopia, and/or nystagmus, as well as myopia. All patients also had some form of retinal dystrophy, with retinal atrophy, increased pigment, or macular heterotopia. Three patients had hypotonia, but none had increased serum creatine kinase. Muscle biopsy was not reported. Brain MRI in all patients showed cerebellar dysplasia and cerebellar vermis hypoplasia; 4 had cerebellar cysts. Other more variable features found on brain imaging included elevation or splaying of the superior cerebellar peduncles, enlarged fourth ventricle, short pons, large eyes, and patchy increased periventricular white matter abnormalities.

Inheritance

The transmission pattern of PTBHS in the families reported by Aldinger et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients from 5 unrelated families with Poretti-Boltshauser syndrome, Aldinger et al. (2014) identified homozygous or compound heterozygous mutations in the LAMA1 gene (see, e.g., 150320.0001-150320.0005). All of the mutations resulted in premature termination or a splicing defect, consistent with a loss of function. The mutations were found by whole-exome sequencing. Functional studies of the variants or studies on patient cells were not performed. Aldinger et al. (2014) noted that mutations in other laminin-encoding genes result in a spectrum of brain malformations (see, e.g., LAMB1, 150240 and LAMC3, 604349).