Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Spastic Paraplegia Type 7 (SPG7) are paradigmatic spastic ataxias (SPAX) with suggested white matter (WM) involvement. Aim of this work was to thoroughly disentangle the degree of WM involvement in these conditions, evaluating both macrostructure and microstructure via the analysis of diffusion MRI (dMRI) data. In this multi-center prospective study, ARSACS and SPG7 patients and Healthy Controls (HC) were enrolled, all undergoing a standardized dMRI protocol and a clinimetrics evaluation including the Scale for the Assessment and Rating of Ataxia (SARA). Differences in terms of WM volume or global microstructural WM metrics were probed, as well as the possible occurrence of a spatially defined microstructural WM involvement via voxel-wise analyses, and its correlation with patients' clinical status. Data of 37 ARSACS (M/F = 21/16; 33.4 ± 12.4 years), 37 SPG7 (M/F = 24/13; 55.7 ± 10.7 years), and 29 HC (M/F = 13/16; 42.1 ± 17.2 years) were analyzed. While in SPG7, only a mild mean microstructural damage was found compared to HC, ARSACS patients present a severe WM involvement, with a reduced global volume (p < 0.001), an alteration of all microstructural metrics (all with p < 0.001), without a spatially defined pattern of damage but with a prominent involvement of commissural fibers. Finally, in ARSACS, a correlation between microstructural damage and SARA scores was found (p = 0.004). In ARSACS, but not SPG7 patients, we observed a complex and multi-faced involvement of brain WM, with a clinically meaningful widespread loss of axonal and dendritic integrity, secondary demyelination and, overall, a reduction in cellularity and volume. The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. At least three clinical types have been suggested in untreated individuals: mild (clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities); moderate (clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities); and severe (obvious progression leading to early death from primary central nervous system involvement or infection). Core features of untreated individuals generally include early childhood-onset non-progressive hearing loss, frequent infections due to immunodeficiency, rheumatologic symptoms (especially systemic lupus erythematosus), developmental delay / intellectual disability, low tone, ataxia, spastic paraplegia, psychiatric findings, bone disease (ranging from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis), gastrointestinal dysfunction (including diarrhea, swallowing issues / aspiration, and enlarged liver and spleen), poor growth, eye issues (including tapetoretinal degeneration and optic nerve atrophy), cardiac complications in adults, and pulmonary issues (including parenchymal lung disease). However, with the advent of enzyme replacement therapy, the natural history of this condition may change. Long-term velmanase alfa (VA) treatment outcomes are still being elucidated, but may include improvement in hearing, immunologic profile, and quality of life (improved clinical outcomes for muscle strength). Similarly, affected individuals who underwent hematopoietic stem cell transplantation (HSCT) experienced improvement in development (with preservation of previously learned skills), ability to participate in activities of daily living, stabilization or improvement in skeletal abnormalities, and improvement in hearing ability, although expressive speech and hearing deficiencies remained the most significant clinical problems after HSCT. The diagnosis of alpha-mannosidosis is established in a proband by identification of deficiency of lysosomal enzyme acid alpha-mannosidase (typically 5%-10% of normal activity) in leukocytes or other nucleated cells AND/OR by the identification of biallelic pathogenic variants in MAN2B1 by molecular genetic testing. Targeted therapies: Velmanase alfa (Lamzede®) enzyme replacement therapy (ERT) has been very well tolerated and is now regarded as a standard treatment for alpha-mannosidosis; improvement in both biochemical and functional parameters have been reported in treated individuals. Hematopoietic stem cell transplantation (HSCT) has been offered as a treatment for severe alpha-mannosidosis. While HSCT carries risks, the data suggests it is a feasible therapeutic option for alpha-mannosidosis, with better outcomes achieved by performing it early before complications arise, balancing the risks and benefits. Supportive care: Hearing aids may be helpful for those with sensorineural hearing loss, whereas pressure-equalizing tubes may be helpful for those with conductive hearing loss. Consider palmidronate (Aredia®) monthly or zoledronic acid (Aclasta®) once a year for osteoporosis or osteopenia. Standard treatment for immunodeficiency / recurrent infections, systemic lupus erythematosus, communicating hydrocephalus, ataxia / gait abnormalities, poor weight gain / growth issues, eye/vision issues, cardiac valve dysfunction / dilated cardiomyopathy, recurrent chest infections / respiratory dysfunction, developmental delay / intellectual disability, and psychiatric manifestations. Surveillance: At each visit, measure weight, length/height, head circumference, and BMI; monitor growth pattern, developmental progress, and educational needs; assess for depression, including sleep disturbances, anxiety, &/or findings suggestive of psychosis; assess for new manifestations such as ataxia and gait abnormalities; evaluate for asthenia and signs/symptoms of communicating hydrocephalus; assess for muscle pain, joint aches, reduced range of motion, and bone pain; monitor for diarrhea and for size of the liver and spleen; and assess for the number and type of infections. Every six to 12 months in childhood and annually in adults, assess fine motor function, gross motor function, endurance, and muscle strength and tone by physical therapy; and assess for features of ataxia. Every one to two years, or as clinically indicated in those with hearing aids, perform an audiology evaluation. Every two to five years in children, adolescents, and adults, consider DXA bone densitometry scan to assess for osteopenia or osteoporosis; radiographs of the hips/spine may be indicated. Annually (or as clinically indicated), routine biochemical lab assessment to include liver and kidney health, blood glucose levels, fluid and electrolyte balance, and complete blood count (with platelets); consider immunlobulin levels, ESR and C-reactive protein; pulmonary function tests; and ophthalmology evaluation. At regular intervals based on clinical features, consider endocrinology evaluations, including hormonal and lipid profiles; consider assessment of liver and spleen size through ultrasound or MRI imaging; consider electrocardiogram, 24-hour electrocardiogram, and echocardiogram; consider sleep study. For those on ERT, plasma oligosaccharides to assess treatment response as clinically indicated. Post-HSCT evaluation of standard surveillance per hematologist/oncologist, which may include ongoing assessment for chimerism and enzyme activity if indicated. Evaluation of relatives at risk: Testing of all at-risk sibs of any age (including prenatal diagnosis) is warranted to allow for early diagnosis and targeted treatment of alpha-mannosidosis. Evaluations can include molecular genetic testing if the pathogenic variants in the family are known or assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known. Alpha-mannosidosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. Prenatal testing for a pregnancy at increased risk is possible by assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing once the pathogenic variants have been identified in the family.

Combined oxidative phosphorylation deficiency (COXPD) is a severe disorder with early onset and autosomal recessive inheritance, and has been divided into 51 types (COXPD1-COXPD51). COXPD14 is caused by a mutation in the FARS2 gene, which encodes mitochondrial phenylalanyl-tRNA synthetase (mt-PheRS), an enzyme that transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, an increasing number of FARS2 variations have been subsequently identified, which present three main phenotypic manifestations: early onset epileptic encephalopathy, hereditary spastic paraplegia, and juvenile-onset epilepsy. To our knowledge, no adult cases have been reported in the literature. We report in detail a case of genetically confirmed COXPD14 and review the relevant literature. Approximately 58 subjects with disease-causing variants of FARS2 have been reported, including 31 cases of early onset epileptic encephalopathy, 16 cases of hereditary spastic paraplegia, 3 cases of juvenile-onset epilepsy, and 8 cases of unknown phenotype. We report a case of autosomal recessive COXPD14 in an adult with status epilepticus as the only manifestation with a good prognosis, which is different from that in neonatal or infant patients reported in the literature. c.467C > T (p.T156M) has been previously reported, while c.119_120del (p.E40Vfs*87) is novel, and, both mutations are pathogenic. This case of autosomal recessive COXPD14 in an adult only presented as status epilepticus, which is different from the patients reported previously. Our study expands the mutation spectrum of FARS2, and we tended to define the phenotypes based on the clinical manifestation rather than the age of onset.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetically determined diseases, characterised by progressive spastic paraparesis of the lower limbs, associated with degeneration of the corticospinal tract and the posterior column of the spinal cord. HSP occurs worldwide and the estimated prevalence is about 1-10/100,000, depending on the geographic localisation. More than 70 genes responsible for HSP have been identified to date, and reports of new potentially pathogenic variants appear regularly. All possible patterns of inheritance (autosomal dominant, autosomal recessive, X-linked and mitochondrial) have been described in families of HSP patients. Among the autosomal recessive forms of HSP (AR-HSP), hereditary spastic paraplegia type 11 is the most common one. We present a patient with diagnosed HSP 11, with a typical clinical picture and characteristic features in additional diagnostic tests.