Moyamoya Disease 6 with Achalasia Due to GUCY1A3 Mutation in a Child
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.299171
Source of Support: None, Conflict of Interest: None
Moyamoya disease is an important cause of arteriopathy in children. It is a progressive vasculopathy characterized by occlusion of the terminal portion of internal carotid arteries and its branches leading to compensatory neovascularization. Moyamoya syndrome may be idiopathic or associated with other conditions such as neurofibromatosis type 1, trisomy 21, Alagille syndrome, sickle cell anemia, post-irradiation.
Here, we describe a 1-year-old girl who was diagnosed to have moyamoya disease 6 with achalasia cardia due to GUCY1A3 mutation.
A 1-year-old girl child born to consanguineous parents presented with complaints of recurrent vomiting and failure to thrive since five months of age. Barium swallow and esophageal manometry were consistent with achalasia cardia. The child underwent laparoscopic Heller's cardiomyotomy with fundoplication. There was documented weight gain after the surgery.
Six weeks later, the child presented with acute onset of weakness of left upper and lower limbs. There was no history of cranial nerve palsy or altered sensorium or seizures. The child was able to swallow food without difficulty. Neurological examination revealed left hemiparesis. Magnetic resonance imaging brain showed acute infarct in the right precentral, right premotor gyrus, and right paracentral lobule without hemorrhagic transformation. There was mild atrophy with gliosis of the left middle frontal gyrus, inferior frontal gyrus, left perirolandic gyrus, left insula, and putamen suggestive of previous ischemic insult. Magnetic Resonance Angiogram [Figure 1] showed narrowing of the bilateral supracondylar internal carotid artery and proximal P1 segment of bilateral posterior cerebral artery suggestive of moyamoya disease.
The possibility of moyamoya disease 6 with achalasia was considered and the blood sample was sent for genetic confirmation. Clinical exome confirmed homozygous mutation in GUCY1A3 gene. The child was started on low-dose aspirin. On follow-up, left hemiparesis improved. Neurosurgeon has suggested close neurological follow-up and decision on revascularization surgery if needed.
Hereditary moyamoya syndrome constitutes a heterogeneous group that includes mendelian and non-mendelian genetic causes. Herve et al. reported nine patients from three consanguineous families with a disorder characterized by early-onset achalasia and an angiopathy consistent with moyamoya disease. The transmission pattern was consistent with autosomal recessive inheritance. In the affected members, three different homozygous truncating mutations in the GUCY1A3 gene were identified. GUCY1A3 encodes the α1 subunit of sGC, which pairs with the β1 subunit encoded by GUCY1B3 to make the heterodimeric enzyme subunit. The isoform is abundantly expressed in vascular SMCs, where it regulates SMC relaxation and vascular tone. Herve et al. hypothesized that disruption of the nitric oxide/guanylate cyclase receptor/cGMP pathway may lead to abnormal vascular remodeling at sensitive sites with disrupted laminar flow, such as the bifurcation of the internal carotid arteries. The achalasia may have resulted from failure of the NO signaling pathway to relax the lower esophageal sphincter. Other features such as hypertension and vasomotor dysfunction like Raynaud phenomenon have been reported.
Wallace et al. identified two patients with compound heterozygous loss of function mutation in the same gene. One patient presented with achalasia at four years of age and later moyamoya disease at 18 years of age. The other patient was a 3-year-old child who presented with moyomoya disease associated with hypertension at 20 months of age, and there was no associated achalasia.
To conclude, in any child who presents with moyamoya, an initial assessment to rule out syndromic forms should be done. In the absence of any known syndromic findings, testing for panel of genes associated with moyamoya disease should be considered. The presence of associated achalasia should prompt evaluation for GUCY1A3 mutation.
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