Primary familial brain calcification with mild phenotype due to a new PDGFB mutation.

INTRODUCTION: Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder that presents cognitive and movement impairment. To diagnose PFBC, both brain calcium accumulations visible at computed tomography (CT) and autosomal dominant or recessive inherited genetic mutation(s) in one of the known genes have to be detected. We describe the case of a female patient aging 62, who presents marked calcifications at brain CT, not due to vitamin D deficiency. These data generated the suspect of PFBC. The patient has two young sons. MATERIALS AND METHODS: The patient first, and her two sons later, underwent clinical and neurological examinations, brain CT, and blood draw for genetic analysis at our clinic. RESULTS: Patient's neurological exams detected gait impairment and tremor of the hands. Brain CT showed calcification of the basal ganglia, cerebellar dentate nuclei, and white matter. Laboratory exams identified high serum parathormone (PTH) and low plasmatic levels of vitamin D; supplementation with vitamin D normalized PTH values. Genetic analysis of the known PFBC-causing genes uncovered a new pathogenic mutation in PDGFB. The same calcifications and genetic variant were found in her younger son. DISCUSSION: Our report presents the case of a patient mildly affected by PFBC due to a novel PDGFB mutation that could have been mistaken with hyperparathyroidism if any further investigations had not been performed. Her younger asymptomatic son bore the same calcification and mutation of the mother, highlighting the importance of family pedigree collection and early diagnosis for prevention of symptoms' onset with future treatments.

Neuromuscular excitability changes produced by sustained voluntary contraction and response to mexiletine in myotonia congenita.

OBJECTIVE: To investigate the cause of transient weakness in myotonia congenita (MC) and the mechanism of action of mexiletine in reducing weakness. METHODS: The changes in neuromuscular excitability produced by 1min of maximal voluntary contractions (MVC) were measured on the amplitude of compound muscle action potentials (CMAP) in two patients with either recessive or dominant MC, compared to control values obtained in 20 healthy subjects. Measurements were performed again in MC patients after mexiletine therapy. RESULTS: Transient reduction in maximal CMAP amplitude lasting several minutes after MVC was evident in MC patients, whereas no change was observed in controls. Mexiletine efficiently reduced this transient CMAP depression in both patients. DISCUSSION: Transient CMAP depression following sustained MVC may represent the electrophysiological correlate of the weakness clinically experienced by the patients. In MC, the low chloride conductance could induce self-sustaining action potentials after MVC, determining progressive membrane depolarization and a loss of excitability of muscle fibers, thus resulting in transient paresis. Mexiletine may prevent conduction block due to excessive membrane depolarization, thus reducing the transient CMAP depression following sustained MVC.

Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease.

Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.