Spastic Paraplegia 9a, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant spastic paraplegia-9A (SPG9A) is caused by heterozygous mutation in the ALDH18A1 gene (138250) on chromosome 10q24.

Homozygous mutation in the ALDH18A1 gene can cause autosomal recessive spastic paraplegia-9B (616586).

Description

Autosomal dominant spastic paraplegia-9A is a neurologic disorder characterized by onset of slowly progressive spasticity mainly affecting the lower limbs. The age at onset usually ranges from adolescence to adulthood, and patients have gait difficulties, motor neuropathy, and dysarthria. Additional variable features include cerebellar signs, cataract, pes cavus, and urinary urgency (summary by Coutelier et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Clinical Features

Slavotinek et al. (1996) presented a 4-generation family in which affected individuals had cataracts, a motor neuronopathy with upper motor neuron signs, short stature, developmental delay, and skeletal abnormalities. In the affected females, weakness developed during pregnancy and resolved after delivery. The condition was inherited in an autosomal dominant manner with an instance of male-to-male transmission in the first 2 generations. Bilateral lamellar cataracts were noted in the first year or so of life and lensectomy was performed early. Delayed bone age, shallow acetabulum, and small carpal bones were described. Poor muscle mass, weakness of the distal muscle groups in the arms and the proximal muscle groups in the lower limbs was observed. Dysplastic base of the skull was also mentioned as a feature in a woman who developed weakness and wasting in the small muscles of her hands at 7 months of pregnancy. With the proband a benign form of muscular atrophy was considered but abandoned when the weakness improved and the patient recovered with no weakness and normal reflexes at 6 months after delivery. A similar illness was noted during her second pregnancy. The products of both the pregnancies were affected. Anticipation was thought to occur in this family. The proband had neurologic signs in his first year of life, whereas his mother's symptoms were first apparent at age 22 years, and in the preceding generation, an affected member presented with weak legs at age 37 years. Several of the affected members were under the 3rd centile for height; the mother of the proband was 147.5 cm tall at the age of 32 years and had a short fifth finger with clinodactyly.

The disorder described here and designated SPG9 is a complicated form of spastic paraparesis. Seri et al. (1999) reported ocular abnormalities occurred in all affected individuals in a large Italian pedigree, with the exception of one who presented with myopia and chorioretinal dystrophy. Furthermore, all subjects presented with persistent vomiting, and in 2 of them, gastroesophageal reflux was diagnosed. The presence of hiatal hernia was ascertained by esophageal endoscopy in 4 affected subjects. Spastic paraparesis showed incomplete penetrance and/or variable expressivity. Pes cavus and the Babinski sign, along with different degrees of muscle wasting in the hands and forelegs, were present in some subjects. Electrophysiologic studies confirmed involvement of the central motor pathways and revealed a peripheral neuropathy that involved mainly the motor axons. Spastic paraparesis appeared in the first and in the third decade of life in different members of the family, with some indications of anticipation. One patient presented with difficulties with ambulation in later adulthood only. His daughter manifested muscle weakness and difficulties walking during pregnancy, at age 25 years. By the age of 35 years, she had severe impairment of ambulation. Her son showed gait disturbances and pes cavus at the age of 4 years.

Coutelier et al. (2015) reported 15 patients from 3 unrelated families with SPG9A. Clinical details were available for 13 patients. Age at onset was variable; most patients had onset between 13 and 60 years, although 1 had onset in infancy. Patients had slowly progressive gait difficulty due to spasticity associated with hyperreflexia in the upper and lower limbs, extensor plantar responses, muscle weakness, and pes cavus. Less common features included decreased vibration sense at the ankles, cerebellar signs, urinary urgency or incontinence, dysarthria, and cataracts. Biochemical studies of 4 patients from 2 unrelated families showed low or borderline levels of citrulline, proline, ornithine, and arginine. Two patients with sporadic occurrence of a similar disorder were also reported. Coutelier et al. (2015) speculated that the abnormal metabolism of certain amino acids may underlie the pathophysiology of this disorder.

Inheritance

The transmission pattern of SPG9A in the families reported by Slavotinek et al. (1996), Seri et al. (1999), and Coutelier et al. (2015) was consistent with autosomal dominant inheritance.

Mapping

In a large Italian pedigree with a new form of rare, autosomal dominant spastic paraparesis, seemingly identical to the disorder in the family reported by Slavotinek et al. (1996), Seri et al. (1999) used a genomewide mapping approach to map the disorder to 10q23.3-q24.2, in a 12-cM region. They pointed out that several neurologic disorders map to the same region: Ochoa syndrome (236730), infantile-onset spinocerebellar ataxia (271245), also called spinocerebellar atrophy-8, and progressive external ophthalmoplegia (PEO; 157640), a condition that appears to involve 'cross-talk' between the nuclear and mitochondrial DNA.

Molecular Genetics

In affected members of 3 unrelated families with autosomal dominant spastic paraplegia-9A, Coutelier et al. (2015) identified heterozygous missense mutations in the ALDH18A1 gene (138250.0007-138250.0009). Two patients with sporadic occurrence of the disorder also carried heterozygous missense variants in ALDH18A1. The mutations were found by whole-exome sequencing or panel sequencing and segregated with the disorder in the families. Fibroblasts from 2 patients of 1 family with the V120A mutation (138250.0008) showed decreased (42%) residual flux of proline biosynthesis compared to controls, consistent with an enzymatic deficiency. Functional studies of the other variants were not performed.

Panza et al. (2016) identified heterozygous missense mutations in the ALDH18A1 gene in affected members of 2 additional families with autosomal dominant SPG9A (138250.0006 and 138250.0007) previously reported by Seri et al. (1999) and Slavotinek et al. (1996), respectively. The mutations were found by candidate gene sequencing and segregated with the disorder in the families. In vitro functional expression assays showed that the mutant proteins localized normally to the mitochondria, but had low P5CS enzymatic activity. Chromatography studies indicated that the mutations disturbed the architecture of the P5CS hexamer, putatively resulting in a dominant-negative effect.