ABSTRACT
Neurodegenerative diseases (ND) affect distinct populations of neurons and manifest various clinical and pathological symptoms. A subset of ND prognoses has been linked to vascular risk factors. Consequently, the current study investigated retinal vascular abnormalities in a murine model of Lafora neurodegenerative disease (LD), a fatal and genetic form of progressive myoclonus epilepsy that affects children. Here, arterial rigidity was evaluated by measuring pulse wave velocity and vasculature deformations in the retina. Our findings in the LD mouse model indicate altered pulse wave velocity, retinal vascular thinning, and convoluted retinal arteries.
Subject(s)
Disease Models, Animal , Lafora Disease , Retinal Vessels , Animals , Lafora Disease/genetics , Lafora Disease/pathology , Lafora Disease/physiopathology , Mice , Retinal Vessels/pathology , Mice, Inbred C57BL , Male , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/physiopathology , Myoclonic Epilepsies, Progressive/pathologyABSTRACT
Mutations in ASAH1 have been linked to two allegedly distinct disorders: Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). We have previously reported FD-like phenotypes in mice harboring a single amino acid substitution in acid ceramidase (ACDase), P361R, known to be pathogenic in humans (P361R-Farber). Here we describe a mouse model with an SMA-PME-like phenotype (P361R-SMA). P361R-SMA mice live 2-3-times longer than P361R-Farber mice and have different phenotypes including progressive ataxia and bladder dysfunction, which suggests neurological dysfunction. We found profound demyelination, loss of axons, and altered sphingolipid levels in P361R-SMA spinal cords; severe pathology was restricted to the white matter. Our model can serve as a tool to study the pathological effects of ACDase deficiency on the central nervous system and to evaluate potential therapies for SMA-PME.
Subject(s)
Farber Lipogranulomatosis , Muscular Atrophy, Spinal , Myoclonic Epilepsies, Progressive , Humans , Mice , Animals , Farber Lipogranulomatosis/genetics , Farber Lipogranulomatosis/metabolism , Farber Lipogranulomatosis/pathology , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Sphingolipids/metabolism , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/pathology , PhenotypeABSTRACT
Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a-/- mice by examining knockout (KO; Epm2a-/-) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a-/- mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models.
Subject(s)
Lafora Disease , Myoclonic Epilepsies, Progressive , Mice , Animals , Lafora Disease/genetics , Lafora Disease/pathology , Disease Models, Animal , Retina/pathology , Myoclonic Epilepsies, Progressive/pathology , ElectroretinographyABSTRACT
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene, a previously reported pathogenic variant, c.125C>T (p.Thr42Met), and a novel likely pathogenic variant c.109C>A (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments.
Subject(s)
Motor Neuron Disease , Muscular Atrophy, Spinal , Myoclonic Epilepsies, Progressive , Humans , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/diagnosis , Myoclonic Epilepsies, Progressive/pathology , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/therapy , MutationABSTRACT
Lafora body disease (LBD) is a progressive myoclonic genetic epilepsy syndrome characterized by the presence of Lafora inclusion bodies within neurons and other cells. It is a complex neurodegenerative disease presenting in adolescence with seizures, myoclonus, and rapid cognitive decline. Diagnosis is often challenging requiring a thorough history including family history, identification of Lafora bodies in apocrine sweat glands of axillary skin, and specific DNA sequencing. There is no cure and management is mainly supportive. We present one of the only few cases from Pakistan of LBD based on characteristic biopsy findings, history of similar ailment in siblings, and EPM2B mutation. This case emphasizes the need for physicians and neurologists to be aware of diagnostic challenges associated with LBD and its characteristic findings. Key Words: Lafora body, Progressive epilepsy, Myoclonus, Axillary skin biopsy, EPM2B.
Subject(s)
Lafora Disease , Myoclonic Epilepsies, Progressive , Neurodegenerative Diseases , Adolescent , Humans , Inclusion Bodies/pathology , Lafora Disease/diagnosis , Lafora Disease/genetics , Lafora Disease/pathology , Myoclonic Epilepsies, Progressive/pathology , Neurodegenerative Diseases/pathologyABSTRACT
The presence of polyglutamine-immunoreactive deposits in neurons of the neostriatum has been reported in dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and Huntington disease (HD). However, among these diseases, precise quantitative investigations on neurons have been performed only for HD. Changes in the number of neurons and the immunohistological features of polyglutamine deposits in the caudate head and putamen were examined in six patients with DRPLA, three with MJD, and four with HD. In the neostriatum in DRPLA, the numbers of large and small neurons were reduced to 33-38% and 48-68% relative to controls, respectively, whereas the corresponding figures in MJD were 19-26% and 65-76%, respectively, and those in HD were 34-35% and 12-16%, respectively. In DRPLA, 2-55% of neurons remaining in the neostriatum showed diffuse nuclear accumulation of polyglutamine, in contrast to 3-20% in MJD and a few percent in HD. These findings indicate that, in the neostriatum, a decrease in the number of small neurons is predominant in HD, whereas a decrease in the number of large neurons is predominant in DRPLA and MJD. Thus, it is suggested that disease processs differ among polyglutamine diseases.
Subject(s)
Huntington Disease , Machado-Joseph Disease , Myoclonic Epilepsies, Progressive , Humans , Huntington Disease/pathology , Myoclonic Epilepsies, Progressive/pathology , Neostriatum/pathology , Neurons/pathology , PeptidesABSTRACT
BACKGROUND: Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ. CASE PRESENTATION: Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease. CONCLUSIONS: In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.
Subject(s)
Myoclonic Epilepsies, Progressive , Genetic Association Studies , Humans , Lysosomal Membrane Proteins/genetics , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/pathology , Phenotype , Receptors, Scavenger/geneticsABSTRACT
Progressive myoclonic epilepsy is a group of neurodegenerative diseases with complex clinical and genetic heterogeneity, which is associated with spontaneous or action-induced myoclonus and progressive neurodegeneration. Since 2020, 4 families with progressive myoclonic epilepsy-11 [OMIM#618876] have been reported with a very limited spectrum of SEMA6B pathogenic variants. In our study, whole-exome sequencing was used in a proband from a nonconsanguineous Chinese family presenting with growth retardation and recurrent atonic seizures. A deletion mutation (c.1960_1978del, p.Leu654Argfs*25) in the last exon of SEMA6B was detected, which is a de novo variant and pathogenic. The new genetic evidence we reported here strengthened the gene-disease relationship, and the gene curation level between SEMA6B and progressive myoclonic epilepsy-11 became "strong" following the ClinGen SOP. Therefore, the results of this study broaden the mutation spectrum of SEMA6B in different ethnic groups and strengthen the gene-disease relationship between SEMA6B and progressive myoclonic epilepsy-11.
Subject(s)
Myoclonic Epilepsies, Progressive/genetics , Semaphorins/genetics , Child , Female , Gene Deletion , Humans , Myoclonic Epilepsies, Progressive/pathology , PhenotypeABSTRACT
Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clinical, biomarker and genetic spectrum of 15 Egyptian children from 14 unrelated families with biallelic pathogenic variants in ASAH1 (12 Farber and 3 SMA-PME). Recruited children were nine females/six males ranging in age at diagnosis from 13 to 118 months. We detected ASAH1 pathogenic variants in all 30 alleles including three novel variants (c.1126A>G (p.Thr376Ala), c.1205G>A (p.Arg402Gln), exon-5-deletion). Both total C26-Ceramide and its trans- isomer showed 100% sensitivity for the detection of ASAH1-related disorders in tested patients. A 10-year-old girl with the novel variant c.1205G>A (p.Arg402Gln) presented with a new peculiar phenotype of PME without muscle atrophy. We expanded the phenotypic spectrum of ASAH1-related disorders and validated the biomarker C26-Ceramide for supporting diagnosis in symptomatic patients.
Subject(s)
Acid Ceramidase/genetics , Distal Myopathies/genetics , Farber Lipogranulomatosis/complications , Myoclonic Epilepsies, Progressive/genetics , Myoclonus/congenital , Child, Preschool , Distal Myopathies/complications , Distal Myopathies/pathology , Exons/genetics , Farber Lipogranulomatosis/genetics , Farber Lipogranulomatosis/pathology , Female , Humans , Infant , Male , Muscular Atrophy, Spinal/complications , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Mutation/genetics , Myoclonic Epilepsies, Progressive/complications , Myoclonic Epilepsies, Progressive/pathology , Myoclonus/complications , Myoclonus/genetics , Myoclonus/pathology , PhenotypeABSTRACT
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG nucleotide repeat expansion in atrophin 1. A previous report described cerebellar white matter lesions on magnetic resonance imaging (MRI) in elderly-onset DRPLA patients, but this finding has not been fully investigated in a total population of DRPLA patients, including juvenile or early-adult onset patients. Herein, we attempted to determine the frequency, distribution pattern, and features of the cerebellar white matter lesions in 30 consecutive DRPLA patients. We also assessed the relationships between the cerebellar white matter lesions and clinical parameters and other MRI findings. The cerebellar white matter lesions were found in 43% of the 30 DRPLA patients, and in 70% of the late adult-onset DRPLA patients. In approx. Two-thirds of the patients with cerebellar white matter lesions, the lesions were localized in the paravermal area (paravermal lesions). Multiple logistic regression analyses revealed that the Fazekas grade of 'cerebral' white matter lesions was independently associated with 'cerebellar' white matter lesions. In conclusion, cerebellar white matter lesions are one of the distinctive MRI features in DRPLA patients, especially in patients with older age at onset. Cerebellar white matter lesions, as well as cerebral white matter lesions, might originate from the disease process of DRPLA itself, and they often have a characteristic distribution of paravermal lesions.
Subject(s)
Myoclonic Epilepsies, Progressive , White Matter , Adult , Aged , Atrophy/pathology , Cerebellum/diagnostic imaging , Cerebellum/pathology , Humans , Magnetic Resonance Imaging , Myoclonic Epilepsies, Progressive/diagnostic imaging , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/pathology , White Matter/diagnostic imagingSubject(s)
Myoclonic Epilepsies, Progressive/genetics , Neuropeptides/genetics , Serpins/genetics , Unverricht-Lundborg Syndrome/genetics , Child , Corpus Callosum/diagnostic imaging , Humans , Magnetic Resonance Imaging , Mutation/genetics , Myoclonic Epilepsies, Progressive/pathology , Unverricht-Lundborg Syndrome/pathology , NeuroserpinABSTRACT
INTRODUCTION: In 2011, a homozygous mutation in GOSR2 (c.430G > T; p. Gly144Trp) was reported as a novel cause of Progressive Myoclonus Epilepsy (PME) with early-onset ataxia. Interestingly, the ancestors of patients originate from countries bound to the North Sea, hence the condition was termed North Sea PME (NSPME). Until now, only 20 patients have been reported in literature. Here, we provide a detailed description of clinical and neurophysiological data of seventeen patients. METHODS: We collected clinical and neurophysiological data from the medical records of seventeen NSPME patients (5-46 years). In addition, we conducted an interview focused on factors influencing myoclonus severity. RESULTS: The core clinical features of NSPME are early-onset ataxia, myoclonus and seizures, with additionally areflexia and scoliosis. Factors such as fever, illness, heat, emotions, stress, noise and light (flashes) all exacerbated myoclonic jerks. Epilepsy severity ranged from the absence of or incidental clinical seizures to frequent daily seizures and status epilepticus. Some patients made use of a wheelchair during their first decade, whereas others still walked independently during their third decade. Neurophysiological features suggesting neuromuscular involvement in NSPME were variable, with findings ranging from indicative of sensory neuronopathy and anterior horn cell involvement to an isolated absent H-reflex. CONCLUSION: Although the sequence of symptoms is rather homogeneous, the severity of symptoms and rate of progression varied considerably among individual patients. Common triggers for myoclonus can be identified and myoclonus is difficult to treat; to what extent neuromuscular involvement contributes to the phenotype remains to be further elucidated.
Subject(s)
Disease Progression , Myoclonic Epilepsies, Progressive/physiopathology , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Cohort Studies , Electroencephalography , Electromyography , Female , Humans , Male , Middle Aged , Mobility Limitation , Mutation, Missense , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/metabolism , Myoclonic Epilepsies, Progressive/pathology , Neural Conduction/physiology , North Sea , Qb-SNARE Proteins , Severity of Illness Index , Young AdultABSTRACT
Action myoclonus - renal failure is a rare syndrome associated with a progressive myoclonic epilepsy and renal impairment that may lead to end-stage renal failure. It is an autosomal recessive genetic disease related to a loss-of-function mutation in SCARB2, which encodes for lysosomal integral membrane protein type 2. Renal involvement is poorly described, and we report here the first electron microscopy renal analysis after having performed a kidney biopsy in a 31-year-old Gambian patient.
Subject(s)
Kidney/pathology , Myoclonic Epilepsies, Progressive/pathology , Adult , Female , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kidney/ultrastructureABSTRACT
Polyglutamine (polyQ) diseases are a group of hereditary neurodegenerative disorders caused by expansion of unstable polyQ repeats in their associated disease proteins. To date, the pathogenesis of each disease remains poorly understood, and there are no effective treatments. Growing evidence has indicated that, in addition to neurodegeneration, polyQ-expanded proteins can cause a wide array of abnormalities in peripheral tissues. Indeed, polyQ-expanded proteins are ubiquitously expressed throughout the body and can affect the function of both the central nervous system (CNS) and peripheral tissues. The peripheral effects of polyQ disease proteins include muscle wasting and reduced muscle strength in patients or animal models of spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxia type 17 (SCA17). Since skeletal muscle pathology can reflect disease progression and is more accessible for treatment than neurodegeneration in the CNS, understanding how polyQ disease proteins affect skeletal muscle will help elucidate disease mechanisms and the development of new therapeutics. In this review, we focus on important findings in terms of skeletal muscle pathology in polyQ diseases and also discuss the potential mechanisms underlying the major peripheral effects of polyQ disease proteins, as well as their therapeutic implications.
Subject(s)
Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Peptides/metabolism , Animals , Bulbo-Spinal Atrophy, X-Linked/metabolism , Bulbo-Spinal Atrophy, X-Linked/pathology , Humans , Huntingtin Protein/metabolism , Huntington Disease/metabolism , Huntington Disease/pathology , Muscular Atrophy/metabolism , Muscular Atrophy/pathology , Myoclonic Epilepsies, Progressive/metabolism , Myoclonic Epilepsies, Progressive/pathology , Peptides/genetics , Spinocerebellar Ataxias/metabolism , Spinocerebellar Ataxias/pathologyABSTRACT
Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease-modifying or curative treatments are currently available. Methods: We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or ATN1 over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements. Results: Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study. Discussion: DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment.
Subject(s)
Disease Management , Myoclonic Epilepsies, Progressive , Adult , Animals , Brain/diagnostic imaging , Child , Disease Models, Animal , Female , Humans , Male , Myoclonic Epilepsies, Progressive/diagnostic imaging , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/pathology , Myoclonic Epilepsies, Progressive/physiopathology , Nerve Tissue Proteins/genetics , Peptides/genetics , PubMed/statistics & numerical dataSubject(s)
Epidermis/pathology , Lafora Disease/pathology , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/pathology , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Adolescent , Biopsy, Needle , Diagnosis, Differential , Disease Progression , Humans , Immunohistochemistry , Lafora Disease/genetics , Male , Myoclonic Epilepsies, Progressive/diagnosis , Prognosis , Risk AssessmentABSTRACT
INTRODUCTION: Patients with dentatorubral-pallidoluysian atrophy (DRPLA) sometimes elicit psychosis. First-generation antipsychotic drugs have been reported to be effective in treating psychotic symptoms associated with the disease. However, little information is available on the benefits of second-generation antipsychotic drugs (SGAs). CASE: We report on a 47-year-old man with DRPLA whose psychotic symptoms were effectively treated with quetiapine, one of the SGAs. He suffered from delusions, auditory hallucinations, and disorganized speech. Initially, other antipsychotic drugs were tried, but were withdrawn because of adverse effects before switching to quetiapine. CONCLUSION: Our observations add to the notion that some of the SGAs are useful for ameliorating psychosis in DRPLA.
Subject(s)
Antipsychotic Agents/therapeutic use , Myoclonic Epilepsies, Progressive/complications , Psychotic Disorders/drug therapy , Quetiapine Fumarate/therapeutic use , Antipsychotic Agents/administration & dosage , Humans , Male , Middle Aged , Myoclonic Epilepsies, Progressive/pathology , Psychotic Disorders/etiology , Psychotic Disorders/pathology , Quetiapine Fumarate/administration & dosageABSTRACT
Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.