Late-onset spinal muscular atrophy associated with the VAPB gene is a slowly progressing, adult-onset, lower motor neuron disease with an autosomal dominant inheritance pattern. We present a male with progressive weakness beginning at age 44, predominantly in the proximal legs, fasciculations, and gait disturbance, with similar clinical syndrome in his mother. On physical examination, he presented weakness in 4 extremities, predominantly proximal, with atrophy and areflexia. The genetic study identified the c.166C > T mutation in the VAPB gene. The P56S mutation of the VAPB gene is associated with adult-onset spinal muscular atrophy and amyotrophic lateral sclerosis; It has been reported in different countries, although the prevalence is higher in Brazil, related to Portuguese migration. Clinically, the patients present with late-onset ALS or SMA. The disease usually onset in the fifth decade of life as progressive weakness, predominantly proximal in the lower extremities, without bulbar or respiratory involvement.

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease. The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. The diagnosis of GARS1-associated axonal neuropathy is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in GARS1 identified by molecular genetic testing. Treatment of manifestations: GARS1-iSMA. Supportive treatment should be tailored to the needs of the affected individual and his/her current functional status (non-sitter, sitter, or walker). A multidisciplinary team to include a neurologist, pulmonologist, physiatrist, and medical geneticist is recommended. GARS1-HMSN. Symptomatic treatment includes facilitating activities of daily living and addressing of mobility needs by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Surveillance: GARS1-iSMA. Routine monitoring of: growth, nutritional status, safety of oral feeding vs gastric tube feeding, respiratory status, need for assistive devices for activities of daily living and mobility, developmental progress and educational needs, and family need for social work support. GARS1-HMSN. Routine monitoring of neurologic findings, physical therapy and occupational therapy needs, and skin for pressure ulcers or sores and skin breakdown (particularly the feet, hips, and other pressure points). Agents/circumstances to avoid: Medications that are toxic or potentially toxic to persons with HMSN. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with GARS1-HMSN in order to identify as early as possible those who would benefit from prompt initiation of symptomatic management and awareness of agents/circumstances to avoid. GARS1-associated axonal neuropathy is an autosomal dominant disorder. GARS1-iSMA. All probands reported to date with the GARS1-iSMA phenotype whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GARS1 pathogenic variant. If the GARS1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. GARS1-HMSN. Most individuals diagnosed with the GARS1-HMSN phenotype have an affected parent. Each child of an individual with GARS1-HMSN is at a 50% risk of inheriting the GARS1 pathogenic variant. Once the GARS1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling.