l-Carnitine prevents oxidative stress in striatum of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload.

The deficiency of the enzyme glutaryl-CoA dehydrogenase leads to predominant accumulation of glutaric acid (GA) in the organism and is known as glutaric acidemia type I (GA1). Despite the mechanisms of brain damage involved in GA1 are not fully understood, oxidative stress may be involved in this process. Treatment is based on protein/lysine (Lys) restriction and l-carnitine (L-car) supplementation. L-car was recently shown to have an important antioxidant role. A knockout mice model (Gcdh-/-) submitted to a dietary overload of Lys was developed to better understand the GA1 pathogenesis. In this study, we evaluated L-car and glutarylcarnitine levels, the lipid and protein damage, reactive oxygen species (ROS) production and antioxidant enzymes activities in striatum of Gcdh-/- and wild-type (WT) mice. We also determined the effect of the L-car treatment on these parameters. Thirty-day-old Gcdh-/- and WT mice were fed a normal chow (0.9% Lys) or submitted to a high Lys diet (4.7%) for 72 h. Additionally, these animals were administered with three intraperitoneal injections of saline or L-car in different times. Gcdh-/- mice were deficient in L-car and presented a higher glutarylcarnitine levels. They also presented lipid and protein damage, an increased ROS production and altered antioxidant enzymes compared to WT mice. Additionally, mice exposed to Lys overload presented higher alterations in these parameters than mice under normal diet, which were significantly decreased or normalized in those receiving L-car. Thus, we demonstrated a new beneficial effect of the L-car treatment attenuating or abolishing the oxidative stress process in Gcdh-/- mice.

Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy.

Alaskan Husky Encephalopathy (AHE) has been previously proposed as a mitochondrial encephalopathy based on neuropathological similarities with human Leigh Syndrome (LS). We studied 11 Alaskan Husky dogs with AHE, but found no abnormalities in respiratory chain enzyme activities in muscle and liver, or mutations in mitochondrial or nuclear genes that cause LS in people. A genome wide association study was performed using eight of the affected dogs and 20 related but unaffected control AHs using the Illumina canine HD array. SLC19A3 was identified as a positional candidate gene. This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. Dogs have two copies of this gene located within the candidate interval (SLC19A3.2 - 43.36-43.38 Mb and SLC19A3.1 - 43.411-43.419 Mb) on chromosome 25. Expression analysis in a normal dog revealed that one of the paralogs, SLC19A3.1, was expressed in the brain and spinal cord while the other was not. Subsequent exon sequencing of SLC19A3.1 revealed a 4bp insertion and SNP in the second exon that is predicted to result in a functional protein truncation of 279 amino acids (c.624 insTTGC, c.625 C>A). All dogs with AHE were homozygous for this mutation, 15/41 healthy AH control dogs were heterozygous carriers while 26/41 normal healthy AH dogs were wild type. Furthermore, this mutation was not detected in another 187 dogs of different breeds. These results suggest that this mutation in SLC19A3.1, encoding a thiamine transporter protein, plays a critical role in the pathogenesis of AHE.

Suspected acquired hypocobalaminaemic encephalopathy in a cat: resolution of encephalopathic signs and MRI lesions subsequent to cobalamin supplementation.

UNLABELLED: PRESENTING SIGNS AND INITIAL INVESTIGATIONS: An 8-year-old female spayed British shorthair cat was presented with a history of waxing and waning neurological signs. Neuroanatomical localisation was consistent with a diffuse forebrain disease. Blood ammonia concentration was increased. Abdominal ultrasonography and a bile acid stimulation test were normal. Magnetic resonance imaging (MRI) revealed hyperintense, bilaterally symmetrical, diffuse lesions on T2-weighted sequences, predominantly, but not exclusively, affecting the grey matter. Serum cobalamin (vitamin B12) concentration was low. Hypocobalaminaemia resulting in a urea cycle abnormality was considered a likely cause of the hyperammonaemia. TREATMENT: Daily cobalamin injections resulted in a rapid clinical improvement. Eight weeks into treatment neurological examination was unremarkable and there was complete resolution of the MRI lesions. CLINICAL IMPORTANCE: This is the first reported case of acquired feline hypocobalaminaemia resulting in an encephalopathy. Additionally, this case is unique in describing reversible brain MRI abnormalities in a cobalamin-deficient companion animal.

Serum D-lactate concentrations in cats with gastrointestinal disease.

BACKGROUND: Increased D-lactate concentrations cause neurological signs in humans with gastrointestinal disease. HYPOTHESIS/OBJECTIVES: To determine if serum D-lactate concentrations are increased in cats with gastrointestinal disease compared to healthy controls, and if concentrations correlate with specific neurological or gastrointestinal abnormalities. ANIMALS: Systematically selected serum samples submitted to the Gastrointestinal Laboratory at Texas A&M University from 100 cats with clinical signs of gastrointestinal disease and abnormal gastrointestinal function tests, and 30 healthy cats. METHODS: Case-control study in which serum D- and L-lactate concentrations and retrospective data on clinical signs were compared between 30 healthy cats and 100 cats with gastrointestinal disease. Association of D-lactate concentration with tests of GI dysfunction and neurological signs was evaluated by multivariate linear and logistic regression analyses, respectively. RESULTS: All 100 cats had a history of abnormal gastrointestinal signs and abnormal gastrointestinal function test results. Thirty-one cats had definitive or subjective neurological abnormalities. D-lactate concentrations of cats with gastrointestinal disease (median 0.36, range 0.04-8.33 mmol/L) were significantly higher than those in healthy controls (median 0.22, range 0.04-0.87 mmol/L; P = .022). L-lactate concentrations were not significantly different between the 2 groups of cats with gastrointestinal disease and healthy controls. D-lactate concentrations were not significantly associated with fPLI, fTLI, cobalamin, folate, or neurological abnormalities (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: D-lactate concentrations can be increased in cats with gastrointestinal disease. These findings warrant additional investigations into the role of intestinal microbiota derangements in cats with gastrointestinal disease, and the association of D-lactate and neurological abnormalities.

Spurious hypercreatininemia: 28 neonatal foals (2000-2008).

OBJECTIVES: To (1) determine the occurrence of spurious hypercreatininemia in a population of hospitalized foals<2 days old, (2) assess the resolution of the hypercreatininemia, and (3) determine its association with survival in these foals. DESIGN: Retrospective case series. SETTING: 2 Referral hospitals. ANIMALS: Foals<2 days old with an admission creatinine>442 micromol/L (>5.0 mg/dL) from 2 referral hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The medical records of 33 foals were reviewed. Twenty-eight had spurious hypercreatininemia and 5 had acute renal failure. Admission creatinine was not significantly different between the 2 groups (mean [standard deviation]). The creatinine was 1,202 micromol/L (663 micromol/L) (13.6 mg/dL [7.5 mg/dL]) versus 1,185 micromol/L (787 micromol/L) (13.4 mg/dL [8.9 mg/d]) (P=0.96) in each group, respectively, though BUN at the time of hospital admission was significantly higher for acute renal failure foals (P=0.009). In the spurious group, serum creatinine at admission decreased to 504 micromol/L (380 micromol/L) (5.7 mg/dL [4.3 mg/dL]) by 24 hours, and to 159 micromol/L (80 micromol/L) (1.8 mg/dL [0.9 mg/dL]) at 48 hours, and to 115 micromol/L (44 micromol/L) (1.3 mg/dL [0.5 mg/dL]) at 72 hours. Twenty-three of 28 foals with spurious hypercreatininemia survived to hospital discharge and there was no difference in mean admission creatinine between survivors (1176 micromol/L [628 micromol/L]) (13.3 mg/dL [7.1 mg/dL]) and nonsurvivors (1308 micromol/L [857 micromol/L]) (14.8 mg/dL [9.7 mg/dL]) (P=0.67). Twenty of 28 foals had clinical signs suggestive of neonatal encephalopathy. CONCLUSION: Creatinine decreased by >50% within the initial 24 hours of standard neonatal therapy and was within the reference interval in all but 1 foal within 72 hours of hospitalization. The diagnosis of neonatal encephalopathy was common in these foals.

Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie.

An eight-month-old Border collie was presented with anorexia, cachexia, failure to thrive and stupor. Laboratory tests demonstrated a mild anaemia, neutropenia, proteinuria and hyperammonaemia. Serum bile acid concentrations were normal, but an ammonia tolerance test (ATT) was abnormal. The dog responded to symptomatic therapy for hepatoencephalopathy. When a low serum cobalamin (vitamin B12) concentration and methylmalonic aciduria were noted, the dog was given a supplement of parenteral cobalamin. Two weeks later, a repeat ATT was normal. Cobalamin supplementation was continued every two weeks, and all clinical signs, except for proteinuria, resolved despite withdrawing all therapy for hepatoencephalopathy. A presumptive diagnosis of hereditary selective cobalamin malabsorption was made, based on the young age, Border collie breed, low serum cobalamin concentration and methylmalonic aciduria. Although hereditary selective cobalamin malabsorption in Border collies, giant schnauzers, Australian shepherd dogs and beagles has previously been reported in North America, to the authors' knowledge this is the first report of the condition in the UK and the first to document an abnormal ATT in a cobalamin-deficient dog.

Encephalopathy with idiopathic hyperammonaemia and Alzheimer type II astrocytes in equidae.

In 3 mature female horses of varying breeds, episodes of colic and depression for 14 days preceded an encephalopathic disorder with maniacal behaviour, anxiety, profuse sweating and, in one case, terminal opisthotonus. Blood ammonia levels were elevated approximately 10-fold. At necropsy, there were gastrointestinal serosal and mesenteric haemorrhages. Histologically, all 3 cases revealed diffuse Alzheimer type II astrocytes in the cerebral grey matter. Alzheimer type II astrocytes were glial fibrillary acidic protein (GFAP) negative or only weakly positive, weakly S-100 positive, and vimentin negative. In the absence of primary hepatic and/or renal lesions, an increase in intestinal ammonia absorption due to ileus or increased ammonia production by colonic bacteria is hypothesised.

Metabolic encephalopathies.

Numerous metabolic derangements originate from outside the CNS that potentially can have a profound effect on cerebral function. The pathogenesis of the resultant dysfunction to the cerebrum and other regions of the brain is extremely varied. However, the CNS can only react in limited ways to these results. Therefore, the veterinarian should recognize the clinical patterns of neurologic signs associated with the metabolic encephalopathies, sift through the multiple potential causes with the aid of other accompanying extracranial clinical signs and clues from biochemical data, understand the underlying pathogenesis of the cerebral dysfunction, and, finally, formulate a rational plan of treatment. Though immediate attention is often directed at restoring homeostasis to the CNS, success is only ultimately achieved via correct and timely treatment of the underlying metabolic disease. Only then does strong potential exist for a permanent reversal of the neurologic deficit.

D-2-hydroxyglutaric aciduria.

Hydroxyglutaric aciduria is detected by gas chromatographic-mass spectrometric analysis, and the D and L forms are quantified by chemical ionization with deuterated internal standards. Patients have recently been described who accumulate the D form, and they appear to be quite different from those with the more common L form. Experience is reported with three patients and an animal model with D-2-hydroxyglutaric aciduria. The phenotype appears to include mental retardation, macrocephaly, hypotonia, seizures, and involuntary movements, although neurologic and systemic manifestations of the disorder varied considerably between individual patients, even within the same family.