ASAH1-related disorders: Description of 15 novel pediatric patients and expansion of the clinical phenotype.

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.

Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content.

The ASAH1 gene encodes acid ceramidase (AC), an enzyme that is implicated in the metabolism of ceramide (Cer). Mutations in the ASAH1 gene cause two different disorders, Farber disease (FD), a rare lysosomal storage disorder, and a rare form of spinal muscular atrophy combined with progressive myoclonic epilepsy (SMA-PME). In the absence of human in vitro neuronal disease models and to gain mechanistic insights into pathological effects of ASAH1 deficiency, we established and characterized a stable ASAH1 knockdown (ASAH1KD) SH-SY5Y cell line. ASAH1KD cells displayed reduced proliferation due to elevated apoptosis and G1/S cell cycle arrest. Distribution of LAMP1-positive lysosomes towards the cell periphery and significantly shortened and less branched neurites upon differentiation, implicate AC for lysosome positioning and neuronal development, respectively. Lipidomic analysis revealed changes in the intracellular levels of distinct sphingolipid species, importantly without Cer accumulation, in line with altered gene transcription within the sphingolipid pathway. Additionally, the transcript levels for Rho GTPases (RhoA, Rac1, and Cdc42), which are key regulators of axonal orientation, neurite branching and lysosome positioning were found to be dysregulated. This study shows the critical role of AC in neurons and suggests how AC depletion leads to defects seen in neuropathology of SMA-PME and FD.

Glycine receptor beta-subunit gene mutation in spastic mouse associated with LINE-1 element insertion.

Congenital myoclonus is a widespread neurologic disorder characterized by hyperexcitability, muscular spasticity and myoclonus associated with marked reduction in neural glycine binding sites. The recessive mouse mutation spastic (spa) is a prototype of inherited myoclonus. Here we show that defects in the gene encoding the beta-subunit of the glycine receptor (Glrb) underlie spa: Glrb maps to the same region of mouse chromosome 3 as spa, and Glrb mRNA is markedly reduced throughout brains of spa mice, most likely as a result of an insertional mutation of a 7.1 kilobase LINE-1 element within intron 6 of Glrb. These results provide evidence that Glrb is necessary for postsynaptic expression of glycine receptor complexes, and suggest Glrb as a candidate gene for inherited myoclonus in other species.

[Case report: congenital myoclonus in a German Holstein calf]. / Fallbericht. Kongenitale Myoklonie bei einem Kalb der Rasse Deutsche Holsteins.

A female German Holstein calf was not able to stand up after birth. Resting the animal was lying in normal position and could lift its head. Sensory stimuli like auditory or tactile impulses induced myoclonic jerking of the whole body. Afterwards it calmed down quickly. The signs observed correspond to the clinical findings of congenital myoclonus in poll Hereford calves. The pathological examination revealed no indications for changes in organs. The inbreeding coefficient of the calf was 1.56 %. The present type of congenital myoclonus in the calf examined is likely to be genetically determined, even if the point mutation in exon 2 of the glycin receptor alpha 1 gene was not confirmed.

Bilateral objective tinnitus secondary to congenital middle-ear myoclonus.

Subjective tinnitus (heard only by the patient) is a common otological complaint. Objective tinnitus (heard by the examiner as well as the patient) is extremely rare. There are only a few cases of objective tinnitus, secondary to middle-ear myoclonus, described in the literature. We present the case of a child with bilateral, congenital, objective tinnitus, secondary to middle-ear myoclonus, with otherwise normal hearing thresholds (250 Hz-8 kHz), and with no evidence of intra-cerebral or systemic disorders. No similar case has been reported in the world literature.

Neonatal sporadic hyperekplexia: a rare and often unrecognized entity.

We report the case of a newborn infant with transient generalized stiffness, obvious from the first days of life, increased muscle tone and repeated myoclonic jerks, who was unsuccessfully treated with phenobarbital until the diagnosis of neonatal sporadic hyperekplexia. To our knowledge this is the first case successfully treated with clobazam, a 1.5 dibenzodiazepine.

[Diagnostic focus on the child with myoclonic seizures in isolation or associated with other types of seizures]. / Enfoque diagnóstico del nino con crisis mioclónicas aisladas o asociadas o otros tipos de crisis.

Myoclonus may be observed in children with mild or severe epileptic syndromes. Both types are seen at characteristic ages, together with other factors: aetiology, family history, hereditary pattern, effect on psychomotor development and EEG-EMG findings. In children with progressive or degenerative encephalopathies and myoclonus, better known as progressive myoclonic epilepsy, there are also specific clinical data, together with biological and genetic markers which permit identification. The most specific clinical characteristics of each of these clinical pictures are described, as are the complementary tests which permit confirmation of these diagnoses.

Neurological diseases of ruminant livestock in Australia. V: congenital neurogenetic disorders of cattle.

As part of a series on neurological disorders in ruminant livestock in Australia, this review focuses on the congenital neurogenic disorders of cattle. The genetic pressures that contribute to the emergence of congenital neurogenic disorders, as well as the methods of diagnosis, are discussed. Disorders reviewed are ordered by breed and include arthrogryposis multiplex, fawn calf syndrome, inherited congenital myoclonus and maple syrup urine disease.

[Dynamics of the clinical and pathologico anatomic changes in spontaneous congenital tremor in swine]. / Dinamika na klinichnite i patologoanatomichnite promeni pri spontanen kongenitalen tremor u svine.

Clinical and morphological studies were carried out on the dynamic of the changes taking place in cases of spontaneous congenital tremor in pigs. It was established that tremor set in immediately after parturition. With the advancement of age the force and intensity of the muscle contractions dropped. The signs of tremor persisted as long as after the fifteenth month of age. The affected animals exhibited delayed growth and development. Morphologically, there was hypoplasia of the cerebellum and the lower portions of the central nervous system. The changes in these organs were found even after the fifteenth month of age.