Type I 3-Methylglutaconic Aciduria (MGCA1) is a metabolic disorder inherited in an autosomal recessive manner. It is caused by a deficiency in the 3-methylglutaconyl-CoA hydratase encoded by the AUH gene, leading to abnormal excretion of urinary organic acids. While the pediatric phenotype encompasses a spectrum ranging from isolated developmental delay to severe forms with leukodystrophy, developmental delay, spastic tetraplegia and movement disorders, the adult phenotype corresponds to a leukodystrophy with spastic ataxia, progressive dementia, and optic neuropathy. Due to its rarity, MGCA1 is most likely underdiagnosed, or diagnosed with an important delay, leading to inadequate care or genetic counselling. A better understanding of the disease's phenotype is thus required to facilitate its clinical and genetic diagnosis, in turn favoring clinical care and genetic counselling. We report two new MGCA1 patients, including an adult male patient with pure, late-onset, and progressive cerebellar ataxia, without optic neuropathy or leukodystrophy. A young female patient case is also reported with moderate developmental delay and leukodystrophy, offering 14-year follow-up data under carnitine supplementation. In both cases, urinary organic acid chromatography was critical to the diagnostic process by demonstrating abnormal and specific urinary organic acids excretion. The description of new, mild and/or late-onset phenotypes expands the clinical and radiological spectrum of MGCA1. Our results show that late-onset MGCA1 patients may present with pure cerebellar ataxia without leukodystrophy, contrasting with current knowledge. These results support the fact that AUH should always be sequenced in patients with pure cerebellar ataxia, but also that urinary organic acid chromatography being a simple, rapid, and cost-effective test, should be performed as a first-tier analysis in all patients with unresolved neurological symptoms. The importance of identifying MGCA1 patients is reinforced by the possibility of implementing a low-risk and possibly effective therapy with low-protein diet and L-carnitine supplementation.

SPG7 mutations are typically associated with autosomal recessive hereditary spastic paraplegia (HSP). However, evidence suggests that the p.A510V variant may also be pathogenic in heterozygous form, often manifesting as late-onset cerebellar ataxia with variable clinical features. We report the case of a 72-year-old woman presenting with progressive gait instability and cerebellar signs. The diagnostic workup included neurological, neurophysiological, radiological, and genetic assessments. Neurological examination revealed gaze-evoked nystagmus, dysarthria, limb dysmetria, and gait ataxia. MRI showed cerebellar atrophy, predominantly involving the vermis. Electrophysiological studies revealed a length-dependent sensory axonal neuropathy. Genetic analysis via NGS detected a heterozygous c.1529C > T (p.A510V) variant in SPG7; no second pathogenic allele or large deletions were identified. Screening for trinucleotide repeat expansions in the most common spinocerebellar ataxias yielded negative results. Segregation analysis was not feasible. The patient remained clinically stable at two-year follow-up. This case contributes to the limited but growing evidence supporting a role for heterozygous SPG7 p.A510V in late-onset cerebellar ataxia without spasticity. Our findings highlight the importance of considering SPG7 in the differential diagnosis of sporadic ataxias, even in the absence of a clear recessive inheritance pattern.

Neurological disorders pose a rapidly growing global health burden, significantly affecting cognitive and motor functions with profound societal repercussions. This comprehensive review probe into the genetic foundations of various neurological conditions while exploring innovative RNA-based therapeutics particularly gene therapies as cutting edge treatment strategies. Through an in-depth analysis of existing literature, the study examines the genetic landscape, disease mechanisms, and gene-based intervention possibilities across a range of neurological disorders, including Cerebellar Ataxias, Autosomal Recessive Ataxia, Mitochondrial Cerebellar Ataxia, Multiple System Atrophy (MSA), Idiopathic Late-Onset Cerebellar Ataxia, Hereditary Spastic Paraplegias, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementias, Inherited Prion Diseases, and Huntington's Disease. It uncovers the intricate network of genetic mutations driving these disorders, shedding light on their mechanisms and uncovering promising therapeutic targets. The review also highlights the remarkable potential of RNA-based therapeutics, with gene therapies standing at the forefront of precision treatment approaches. By offering an up-to-date understanding of the genetic intricacies and emerging therapeutic possibilities in neurological disorders, this study significantly contributes to the advancement of precision medicine in neurology. It also paves the way for future research and clinical applications aimed at improving patient care and outcomes.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder due to mutations in the SACS gene. While the typical phenotype is characterized by cerebellar ataxia, spasticity, and peripheral neuropathy, more reports are published of atypical and late-onset presentations, also lacking typical cerebellar signs of the disease, which can mimic Charcot-Marie-Tooth disease (CMT). We report a 58-year-old Chinese male with a 12-year history of progressive gait instability and lower limb weakness, who also exhibited retinal degeneration. Remarkably, in contrast to the majority of ARSACS patients, he had no significant spasticity, thus expanding the phenotypic spectrum. Genetic analysis identified a pathogenic compound heterozygous mutation in SACS: a novel frameshift variant (c.178del, p.Asp60ThrfsTer8) in exon 4, unreported in ClinVar, and a missense variant (c.4723 C > T, p.Arg1575Trp) in exon 10, documented in ClinVar with conflicting interpretations. The exceptionally late onset in this patient suggests that the c.178del frameshift may partially preserve sacsin function, thereby delaying disease manifestation. MLPA analysis excluded CMT1/HNPP-related rearrangements, confirming an ARSACS diagnosis. Familial segregation further supported autosomal recessive inheritance, emphasizing the importance of family screening. Given this, our case suggests a potential extended therapeutic window in late-onset ARSACS and may need to be included in future therapeutics efforts, emphasizing the importance of identifying such atypical forms. This observation highlights the importance of thorough genetic testing in achieving a correct diagnosis and providing treatment for patients with undiagnosed progressive ataxia. AFG3L2-related neurologic disorders comprise four phenotypes. Spinocerebellar ataxia type 28 (SCA28), the most common phenotype, is characterized by young adult onset (26.5 ± 17.2 years); the onset range is from birth to 74 years of a cerebellar syndrome manifesting initially as very slowly progressive gait and limb ataxia resulting in incoordination and balance problems. Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding. Pyramidal syndrome (increased and brisk reflexes, extensor plantar reflex, and spasticity) is commonly observed in individuals with longer disease duration. Although cognitive impairment, spasticity, and ophthalmologic signs can occur with disease progression, most individuals remain ambulatory and fully independent throughout their lives. Spastic ataxia type 5 (SPAX5), reported in 14 individuals to date, ranges from severe neurodegeneration with microcephaly, poor weight gain, developmental delay, developmental regression around age nine months, and death as early as age 2.5 years. Milder presentations range from onset in infancy to an early-onset complex cerebellar ataxia with myoclonic epilepsy. AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR), reported in two individuals to date, is a late-onset ataxia with a clinical phenotype closely resembling that of SCA28. Optic atrophy type 12 (OPA12) manifests as decreased visual acuity (variable but frequently ranging from 0.2/10 to 2/10), photophobia, and impaired color vision. Ophthalmologic findings are optic nerve pallor and highly reduced retinal nerve fiber layer on optical coherence tomography. Although affected individuals do not present with ataxia, some may exhibit sensorineural hearing loss, neurodevelopmental disorders, dystonia, and spasticity. The diagnoses of SCA28 and OPA12 are established in a proband with suggestive findings and a heterozygous pathogenic variant in AFG3L2 identified by molecular genetic testing. The diagnoses of SPAX5 and AFG3L2-SCAR are established in a proband with suggestive findings and biallelic pathogenic variants in AFG3L2 identified by molecular genetic testing. Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields including neurologists (to address pharmacologic treatment of myoclonic epilepsy, spasticity, movement disorders); occupational therapists (to optimize activities of daily living and home safety); physiatrists and physical therapists (to help maintain independence and mobility); nutritionists and feeding therapy programs (to assess the risks of aspiration and need for gastrostomy tube placement for those with dysphagia); speech-language therapists (to address communication for individuals who have expressive language difficulties), ophthalmologists (to consider surgery for ptosis); low vision clinics (for those with optic atrophy); and social workers and psychologists (depending on any cognitive or psychologic manifestations). Surveillance: Routinely scheduled follow-up appointments with treating clinicians are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Agents/circumstances to avoid: Alcohol consumption and sedatives such as benzodiazepines that may worsen gait ataxia and coordination. Carbamazepine and phenytoin may exacerbate myoclonus in SPAX5. SCA28 and OPA12 are inherited in an autosomal dominant manner. AFG3L2-SCAR and SPAX5 are inherited in an autosomal recessive manner. Autosomal dominant inheritance: Most individuals diagnosed with SCA28, and some individuals diagnosed with OPA12, have an affected parent. Some individuals diagnosed with an autosomal dominant AFG3L2-related neurologic disorder have the disorder as the result of a de novo pathogenic variant. Each child of an individual with an autosomal dominant AFG3L2-related neurologic disorder has a 50% risk of inheriting the pathogenic variant. If the reproductive partner of an individual with an autosomal dominant AFG3L2-related neurologic disorder also has an AFG3L2 pathogenic variant, offspring are at risk of inheriting biallelic pathogenic variants and having an autosomal recessive AFG3L2-related neurologic disorder. Once the AFG3L2 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. Autosomal recessive inheritance: The parents of a child with an autosomal recessive AFG3L2-related neurologic disorder are presumed to be heterozygous for an AFG3L2 pathogenic variant. If both parents are known to be heterozygous for an AFG3L2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial AFG3L2 pathogenic variants. Heterozygous family members of an individual with an autosomal recessive AFG3L2-related neurologic disorder are typically asymptomatic and the risk of developing an AFG3L2-related neurologic disorder appears to be low. Once the AFG3L2 pathogenic variants has been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare inherited condition described worldwide and characterized by a wide spectrum of heterogeneity in terms of genotype and phenotype. How sacsin loss leads to neurodegeneration is still unclear, and current knowledge indicates that sacsin is involved in multiple functional mechanisms. We hence hypothesized the existence of epigenetic factors, in particular alterations in methylation patterns, that could contribute to ARSACS pathogenesis and explain the pleiotropic effects of SACS further than pathogenic mutations. To investigate this issue, we recruited eight patients affected by ARSACS, four characterized by early onset of the disease and four with late onset. We performed Whole Genome Bisulfite Sequencing using DNA from peripheral blood to define the methylome of patients and compared them with a control group. Our analysis showed that patients with ARSACS exhibit an altered methylation pattern and that the observed differences exist also among affected individuals with different age of onset. Our study provides valuable insights for employing epigenetic biomarkers to assess the severity and progression of this disorder and propels further investigations into the role of epigenetic processes in ARSACS pathogenesis.