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NEURODEGENERATION, CHILDHOOD-ONSET, WITH ATAXIA, TREMOR, OPTIC ATROPHY, AND COGNITIVE DECLINE; CONATOC

NEURODEGENERATION, CHILDHOOD-ONSET, WITH ATAXIA, TREMOR, OPTIC ATROPHY, AND COGNITIVE DECLINE; CONATOC

Childhood-onset neurodegeneration with ataxia, tremor, optic atrophy, and cognitive decline (CONATOC) is an autosomal recessive progressive disorder with onset o...

Childhood-onset neurodegeneration with ataxia, tremor, optic atrophy, and cognitive decline (CONATOC) is an autosomal recessive progressive disorder with onset of symptoms in the first decade. Brain imaging may show variable features, including leukoencephalopathy and cerebellar atrophy (summary by Fagerberg et al., 2020).

▼ Clinical Features
Fagerberg et al. (2020) reported 4 patients, ranging from 16 to 22 years of age, with a similar childhood-onset neurodegenerative disorder. The patients, who came from 3 unrelated consanguineous families of Turkish or Iraqi descent, were ascertained through collaborative efforts, such as the GeneMatcher and Decipher databases. One of the Turkish patients had previously been reported by Reuter et al. (2017). Most patients had normal early development, although 2 had mild speech delay and some had mildly delayed walking (by 2 years of age). A few had a large head circumference (up to +3 SD), and some had early-onset transient hepatic anomalies, such as neonatal jaundice, hypoglycemia, and hepatic fibrosis that resolved spontaneously. Between 2 and 8 years of age, all developed progressive neurologic symptoms, including swallowing difficulties or drooling, dysarthria, tremor, severe ataxia, optic atrophy, slow saccadic movements, urinary incontinence, muscle weakness, and cognitive decline. IQ measured in 1 patient was 36; at age 15, she functioned at the level of a 3-year-old. Some patients also had more variable features, including facial dyskinesia, strabismus, dystonia, and features of spasticity, such as extensor plantar responses and clonus; 2 patients had bowel incontinence. Brain imaging showed progressive abnormalities, including hypointensities in the globus pallidus with a hyperintensive streak, white matter abnormalities consistent with leukoencephalopathy in the periventricular and cerebellar white matter, and cerebellar atrophy. The younger sib of the patient in family A carried the mutation, but he was presymptomatic at 2.5 years of age. He had mild speech and motor delay and strabismus, as well as febrile seizures. However, none of the other patients had seizures, and his unaffected mother had a history of febrile seizures. Some patients were treated with oral choline supplementation, but the treatment did not result in sustainable improvement.

▼ Inheritance
The transmission pattern of CONATOC in the families reported by Fagerberg et al. (2020) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In 4 affected individuals from 3 unrelated consanguineous families, 2 of Turkish origin and 1 of Iraqi origin, with CONATOC, Fagerberg et al. (2020) identified homozygous frameshift mutations in the SLC44A1 gene (606105.0001-606105.0003). The mutations, which were found by exome or whole-genome sequencing, segregated with the disorder in all families; none were present in the gnomAD database. Fibroblasts derived from 2 unrelated patients showed common ultrastructural abnormalities, including large areas devoid of ribosomes, local accumulation of mitochondria, elongated endoplasmic reticulum, and small vacuoles. The fibroblasts showed significantly reduced choline uptake compared to controls (20-30%). Choline supplementation increased choline transport, increased SLC44A1 mRNA levels, and resolved the morphologic abnormalities in vitro. Detailed studies on patient fibroblasts were consistent with changes in phospholipid metabolism and gene expression. There was reduced de novo synthesis of phosphatidylcholine, although membrane phosphatidylcholine remained stable due to compensatory mechanisms, including release of choline from membrane lipids. However, there were decreased levels of phosphatidylethanolamine and phosphatidylserine, as well as increased iron accumulation in mutant cells. There was also abnormal regulation of genes involved in mitochondrial fatty acid transport and beta-oxidation, and evidence of disturbances in fatty acid homeostasis. Most of these abnormalities were responsive to choline supplementation in vitro. The findings reflected a deficiency in membrane choline transport and lipid and membrane metabolism.

Tags: 9q31.2, 9q31.1