De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy.

BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. METHODS: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. RESULTS: We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. CONCLUSIONS: These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.

Loss of α1ß1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1ß1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.

A novel hereditary extensive vascular leukoencephalopathy mapping to chromosome 20q13.

OBJECTIVE: The detection of a leukoencephalopathy is a frequent situation in neurologic practice. In a number of cases, the etiology remains obscure despite extensive investigations. We characterized the clinical, pathologic, and genetic features of a novel hereditary vascular leukoencephalopathy. METHODS: After the observation of a similar leukoencephalopathy in 2 sisters, clinical, neuroimaging, and molecular genetics investigations were conducted in 21 of their consenting relatives. Pathologic data were obtained in one patient. RESULTS: Fourteen members presented with significant white matter lesions at MRI examination, among whom only 5 individuals were symptomatic. The main clinical manifestations included gait disturbances, transient movement disorders, stroke, and cognitive dysfunction. The 9 remaining members aged from 26 to 60 years were asymptomatic. The MRI pattern was highly stereotyped with symmetric white matter hyperintensities worsening with patient's age. We mapped the gene involved in this condition on chromosome 20q13. Neuropathologic examination suggested that this leukoencephalopathy is underlaid by a cerebral arteriolopathy affecting small preterminal arterioles, clearly distinct from amyloid angiopathy and hypertension-related small-vessel disease. CONCLUSIONS: These data establish that this family is affected by a novel autosomal dominant vascular leukoencephalopathy mapping to chromosome 20q13. This disease is characterized by a progressive and age-related hemispheric and brainstem leukoencephalopathy contrasting with the paucity and late onset of clinical symptoms in most of the cases.