A novel missense variant in the L2HGDH gene in a cat with L-2-hydroxyglutaric aciduria and multicystic cerebral lesions.

CASE DESCRIPTION: A 9-month-old intact male domestic shorthair cat was evaluated for increasing frequency of generalized tonic-clonic seizures. CLINICAL FINDINGS: The cat was reported to have had episodes of circling between the seizures. Upon examination, the cat had bilateral inconsistent menace response but otherwise normal physical and neurological examinations. DIAGNOSTICS: Magnetic resonance imaging (MRI) of the brain identified multifocal, small, rounded intra-axial lesions within the subcortical white matter containing fluid with similar characteristics as cerebrospinal fluid. Evaluation of urine organic acids showed increased excretion of 2-hydroxyglutaric acid. An XM_023255678.2:c.397C>T nonsense variant in the L2HGDH gene encoding L-2-hydroxyglutarate dehydrogenase was identified using whole genome sequencing. TREATMENT AND OUTCOME: Levetiracetam treatment was initiated at 20 mg/kg PO q8h, but the cat died after a seizure 10 days later. CLINICAL RELEVANCE: We report the second pathogenic gene variant in L-2-hydroxyglutaric aciduria in cats and describe for the first time multicystic cerebral lesions on MRI.

L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria.

A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

Clinical features and disease progression of L-2-hydroxyglutaric aciduria in 27 Staffordshire bull terriers.

To describe the development of clinical signs (CS) and outcome of L-2-hydroxyglutaric aciduria (L-2-HGA), owners of 119 Staffordshire bull terriers positive for the known L-2-hydroxyglutarate dehydrogenase autosomal-recessive mutations were requested to complete a questionnaire regarding their pet's CS. Questionnaires were returned for 27 dogs, all with neurological abnormalities-not all questions were answered in all cases. The mean age of CS onset was 12 months (range 2.5-60). Gait dysfunction was reported in 26/26 dogs, with stiffness of all four limbs the most common (24/26) and earliest recognised abnormality. Kyphosis (19/26), body and/or head tremors (19/26) and hypermetria (15/26) were frequent. Behavioural changes were present in 24/27 dogs; most commonly staring into space (21/24), signs of dementia (17/24) and loss of training (15/24). Eighteen dogs demonstrated paroxysmal seizure-like/dyskinetic episodes. Nineteen (70 per cent) dogs were alive at a mean survival time of 76.6 months (12-170) after onset of CS. L-2-HGA was the cause of euthanasia in six dogs. Euthanasia occurred at a mean survival time of 44 months (8.5-93) after onset of CS, with 2/8 dogs euthanased within 12 months. L-2-HGA is considered a progressive neurological disease; however, CS can be successfully managed with affected dogs potentially living a normal lifespan.

Polioencephalomyelopathy in a mixed breed dog resembling Leigh's disease.

A 14-month-old mixed-breed dog was presented with acute onset of exercise intolerance that quickly progressed to quadriparesis. Gross and microscopic autopsy findings indicated a type of degenerative polioencephalomyelopathy resembling subacute necrotizing encephalomyelopathy in dogs or Leigh's disease in humans. This syndrome has previously been reported only in purebred dogs.

Polioencéphalomyélopathie chez un chien de race croisée ressemblant au syndrome de Leigh. Un chien de race croisée âgé de 14 mois a été présenté avec l'apparition aiguë d'intolérance à l'exercice qui a rapidement progressé à la quadriparésie. Suite à la nécropsie, les constatations macroscopiques et microscopique ont indiqué un type de polioencéphalomyélopathie dégénérative ressemblant à l'encéphalomyélopathie nécrosante subaiguë chez les chiens ou au syndrome de Leigh chez les humains. Ce syndrome avait été signalé précédemment seulement chez les chiens de race pure.(Traduit par Isabelle Vallières).

L-2 hydroxyglutaric aciduria in a South African Staffordshire Bull Terrier.

L-2 hydroxyglutaric aciduria is an autosomal recessive error of metabolism that manifests as an encephalopathy. The most common presenting signs are seizures, tremors, ataxia and/ or dementia. Some affected dogs show only subtle behavioural changes. Amongst canines, the condition has been best described in Staffordshire Bull Terriers. Although this is the first reported case in South Africa, at least three other affected dogs have been indentified by polmerase chain reaction (PCR) in this country. Affected dogs have normal haematology, serum biochemistry and routine urine analysis. This report discusses the advantages and limitations of the three main diagnostic modalities, namely: magnetic resonance imaging, urine gas chromatography-mass spectrometry and genetic testing. The aim of this report is to increase awareness of the condition, assist diagnosis in encephalopathic dogs and improve detection of carriers amongst breeding stock.

L-2-hydroxyglutaric aciduria in two female Yorkshire terriers.

Two female Yorkshire terrier puppies were presented with generalized tonic-clonic seizures and ataxia. MRI revealed bilaterally symmetrical, diffuse regions of gray matter hyperintensity on T2-weighted and fluid-attenuated inversion recovery sequences. Urinary organic acids were quantified by gas chromatography-mass spectroscopy and were consistent with a diagnosis of L-2-hydroxyglutaric aciduria (L2HGA). The L2HGDH gene encodes for the enzyme L-2-hydroxyglutarate dehydrogenase, which helps break down L-2-hydroxyglutaric acid. In both puppies described in this report, a homozygous mutation at the translation initiation codon of the homolog canine L2HGDH gene was detected (c.1A>G; p.Met1?), confirming the diagnosis of L2HGA at the DNA level. Canine L2HGA is caused by more than one mutation of L2HGDH, as reported in humans.

A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria.

BACKGROUND: L-2-hydroxyglutaric aciduria is a metabolic repair deficiency characterized by elevated levels of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid. Neurological signs associated with the disease in humans and dogs include seizures, ataxia and dementia. CASE PRESENTATION: Here we describe an 8 month old Yorkshire terrier that presented with episodes of hyperactivity and aggressive behavior. Between episodes, the dog's behavior and neurologic examinations were normal. A T2 weighted MRI of the brain showed diffuse grey matter hyperintensity and a urine metabolite screen showed elevated 2-hydroxyglutaric acid. We sequenced all 10 exons and intron-exon borders of L2HGDH from the affected dog and identified a homozygous A to G transition in the initiator methionine codon. The first inframe methionine is at p.M183 which is past the mitochondrial targeting domain of the protein. Initiation of translation at p.M183 would encode an N-terminal truncated protein unlikely to be functional. CONCLUSIONS: We have identified a mutation in the initiation codon of L2HGDH that is likely to result in a non-functional gene. The Yorkshire terrier could serve as an animal model to understand the pathogenesis of L-2-hydroxyglutaric aciduria and to evaluate potential therapies.

Neuropathological findings in a Staffordshire bull terrier with l-2-hydroxyglutaric aciduria.

l-2-Hydroxyglutaric aciduria (l-2-HGA) is a hereditary neurometabolic disorder reported in human beings and dogs. An 11-month-old Staffordshire bull terrier was suspected to have the disease, on the basis of clinical signs and magnetic resonance imaging findings. l-2-HGA was confirmed by urinary organic analysis and DNA testing and the dog was humanely destroyed. Post-mortem findings consisted only of microscopical lesions in the brain, characterized by marked spongiform changes and predominantly affecting the grey matter of the cerebral cortex, thalamus, cerebellum and brainstem. The spongiform changes were characterized by well-demarcated, clear vacuoles located at perineuronal and perivascular sites. Immunohistochemical and ultrastructural examination confirmed that the affected cells were astrocytes.

A variant form of neuronal ceroid lipofuscinosis in American bulldogs.

Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases characterized by accumulations of autofluorescent lipopigments within cells of the nervous system. Nine related American Bulldogs demonstrated dysmetria in all limbs and paraparesis. Nonambulatory tetraparesis was observed only in the later stages of the disease. The clinical signs developed between 1 and 3 years of age and were slowly progressive over several years, which is inconsistent with most reports in other breeds. Results from blood tests for 8 different lysosomal storage diseases on 4 affected and 6 related but unaffected dogs were negative. Four affected dogs were euthanized and histopathologic examinations showed diffuse accumulations of periodic acid-Schiff-positive inclusions in neurons and axonal spheroids along the entire neuraxis and retinae. The most severe lesions were in the brainstem proprioceptive nuclei and spinal cord, consistent with clinical signs. The storage material was autofluorescent and immunohistochemically positive for products of lipid peroxidation. Ultrastructural analysis was consistent with NCL. Pedigree analysis supports an autosomal-recessive mode of inheritance. NCL has not been previously reported in the American Bulldog and these findings suggest a variant form of the canine disease.