Spinocerebellar Ataxia, Autosomal Recessive 21

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-21 (SCAR21), also known as low gammaglutamyltransferase (GGT) cholestasis, acute liver failure, and neurodegeneration (CALFAN) syndrome, is caused by homozygous mutation in the SCYL1 gene (607982) on chromosome 11q13.

Description

Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by Schmidt et al., 2015).

The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by Lenz et al., 2018).

Clinical Features

Schmidt et al. (2015) reported 2 young adult sibs, born of unrelated parents of European origin, with an early-onset ataxia syndrome. At about 9 months of age, both patients developed recurrent episodes of liver failure, which were mainly associated with fever. The episodes ended later in childhood, but both had chronic fibrotic liver disease and marked hepatosplenomegaly. Both sibs also had delayed early motor milestones and presented in early childhood with an ataxic gait, balance difficulties, and intention tremor, consistent with cerebellar dysfunction. Additional features included muscle atrophy of the upper and lower limbs, weakness of the lower legs associated with foot drop, distal sensory impairment, and hyporeflexia, indicating a hereditary sensorimotor neuropathy. Neurogenic stuttering was also noted. Brain imaging showed selective nonprogressive atrophy of the cerebellar vermis. Brain imaging also suggested subclinical optic atrophy, although visual acuity was preserved. One sib had normal cognition; the other had mildly impaired intellectual development. An unrelated 17-year-old girl of Cuban descent had a similar phenotype with early childhood onset of recurrent episodes of liver failure, progressive gait ataxia, and neurogenic stuttering. At age 10, she was barely able to run. In her teenage years, she developed a predominantly motor neuropathy with distal muscle weakness and atrophy and pes equinus. Nerve conduction studies showed a mixed sensorimotor peripheral neuropathy, and brain imaging showed atrophy of the cerebellar vermis. She also had mild spasticity and hyperreflexia, suggesting pyramidal tract involvement, as well as mild learning disability.

Lenz et al. (2018) reported 7 children from 5 unrelated families with a syndromic form of liver failure with variable neurologic features. The patients, who were all under 12 years of age at the time of the report, were ascertained from a cohort of pediatric patients with unexplained cholestasis or acute liver failure. The patients presented in infancy with episodic acute liver dysfunction, almost always associated with a febrile illness. Three had prior neonatal jaundice. Acute features during infection included jaundice, cholestasis, elevated liver enzymes with lesser elevation of GGT, and hepatomegaly, sometimes with splenomegaly. The laboratory abnormalities tended to resolve within weeks, but all patients developed liver fibrosis. One patient had a liver transplant at 23 months of age. Liver biopsies showed microvesicular steatosis, bridging fibrosis, hepatocyte degeneration, ductal reactions, cholestasis, and disorganized Golgi apparatus. Six patients had mild microcephaly, 6 had mild language delay, 3 had borderline to mildly impaired intellectual impairment, and 1 had severely impaired intellectual development. Motor dysfunction was observed in 5 patients, with highly variable manifestations, including proximal muscle weakness, tremor, and abnormal gait, although none had frank ataxia. One patient had seizures. Five patients had variable skeletal abnormalities, including short stature, hip dysplasia, rib anomalies, scoliosis, and lordosis. Brain imaging was unremarkable in most patients, but 2 sibs had mild cerebral and cerebellar atrophy. The study highlighted the phenotypic variability associated with recessive SCYL1 mutations, prompting the authors to suggest the name 'CALFAN,' for low GGT cholestasis, acute liver failure, and neurodegeneration.

Spagnoli et al. (2019) reported a 7-year-old girl, born of unrelated Italian parents, with SCAR21. Around 2 years of age, she presented with episodic tremor, initially induced by fever, and thereafter showed mild axial hypotonia, broad-based gait, dysmetria, and diffuse tremor. At age 5.5, she developed an ocular motility disorder with upward gaze palsy and oculomotor apraxia. She also had weakness with fatigability and a distal choreic movement disorder affecting the upper limbs. These neurologic symptoms worsened during febrile illness. She also had impaired intellectual development with language involvement. Brain imaging showed mild mild cerebellar atrophy. At age 7, she had hepatosplenomegaly and an axonal motor polyneuropathy; further details on liver involvement were not provided. The authors noted that the patient had recurrent respiratory infections with respiratory insufficiency since infancy.

Inheritance

The transmission pattern of SCAR21 with hepatopathy in the families reported by Schmidt et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with SCAR21, Schmidt et al. (2015) identified compound heterozygous truncating mutations in the SCYL1 gene (607982.0001-607982.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Patient fibroblasts showed absence of the SCYL1 protein and massively enlarged Golgi apparatus.

In 7 patients from 5 unrelated families with a phenotype overlapping SCAR21, termed CALFAN, Lenz et al. (2018) identified homozygous mutations in the SCYL1 gene (see, e.g., 607982.0005-607982.0008). There were 3 nonsense and 2 missense mutations, consistent with a loss of function. The patients, who were all under 12 years of age at the time of the report, were ascertained from a cohort of pediatric patients with unexplained cholestasis or acute liver failure who underwent whole-exome sequencing; the mutations were filtered against public databases. Immunostaining of patient liver tissue showed depletion of SCYL1. Western blot analysis of available patients' fibroblasts showed decreased SCYL1, and functional studies showed impaired retrograde transport from the Golgi, suggesting a defect in intracellular trafficking. However, there was no evidence of ER stress.

In a 7-year-old girl with SCA21, Spagnoli et al. (2019) identified a homozygous frameshift mutation in the SCYL1 gene (607982.0009). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the gnomAD database. It was predicted to result in a loss of protein function. Studies of patient cells were not performed.

Animal Model

Schmidt et al. (2007) found that the autosomal recessive mouse neurodegenerative disorder 'muscle deficient' (mdf) is caused by a homozygous 1-bp insertion (c.1169_1170insT) in exon 8 of the Scyl1 gene, resulting in a loss of function. Mdf mice show progressive neuromuscular atrophy, hindlimb paralysis, and phenotypes consistent with cerebellar involvement, such as gait ataxia, abnormal hindlimb posture, and tremor. Neuropathologic examination of mdf mice showed cerebellar atrophy, Purkinje cell loss, and optic nerve atrophy.

Pelletier et al. (2012) demonstrated that deletion of Scyl1 in mice caused an early-onset progressive motor neuron disease with features characteristic of amyotrophic lateral sclerosis (ALS; 105400). Mutant mice had growth retardation, waddling and abnormal gait, muscle wasting, and progressive motor dysfunction resulting in paralysis of the hind paws. Skeletal muscles of mutant mice showed neurogenic atrophy, fiber type switching, and disuse atrophy, and peripheral nerves showed axonal degeneration and segmental demyelination. There was also a reduction in the number of spinal ventral horn motor neurons, with swollen mitochondria in the remaining neurons and evidence of inflammation. However, there were no major cerebellar changes. Spinal cord ventral neurons from mutant mice showed redistribution of TDP43 (TARDBP; 605078) from the nucleus to cytoplasmic aggregates and the presence of ubiquilin-2 (UBQLN2; 300264) inclusions, as observed in ALS. Neuron-specific depletion, but not muscle-specific depletion, recapitulated the phenotypic changes observed in Slcy1-null mice, suggesting that Scyl1 acts in a neuron-autonomous manner to play a critical role in the survival of large motor neurons.