Limits...
Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis

View Article: PubMed Central - PubMed

ABSTRACT

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical–biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C > A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~ 3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.

No MeSH data available.


Related in: MedlinePlus

Brain MRI of the patients. (A) Brain MRI of patient II-2 at 14 months revealed bilateral signal abnormalities in the globi pallidi and right caudate nucleus. (B) Brain MRI of patient II-4 at 14 months showed bilateral signal abnormalities in the globi pallidi. (C) Brain MRI of patient II-4 at 18 months revealed progression of the pathological lesions, with atrophy of the cortex and enlargement of the ventricles. (D) The brain MRI scan of patient II-4 at 24 months shows improvement in signal abnormalities in the basal ganglia when compared to scans at 14 (B) and 18 (C) months.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5121361&req=5

f0005: Brain MRI of the patients. (A) Brain MRI of patient II-2 at 14 months revealed bilateral signal abnormalities in the globi pallidi and right caudate nucleus. (B) Brain MRI of patient II-4 at 14 months showed bilateral signal abnormalities in the globi pallidi. (C) Brain MRI of patient II-4 at 18 months revealed progression of the pathological lesions, with atrophy of the cortex and enlargement of the ventricles. (D) The brain MRI scan of patient II-4 at 24 months shows improvement in signal abnormalities in the basal ganglia when compared to scans at 14 (B) and 18 (C) months.

Mentions: Patient II-2 was the second child of healthy, nonconsanguineous, Japanese parents. She was born at full term gestation after an uncomplicated pregnancy. Her birth weight was 2714 g, and she measured 44 cm (− 2.6 SD) in length, with an occipitofrontal circumference of 32.5 cm (− 0.5 SD). She could hold her head up at 5 months and roll over at 10 months. At 12 months, she was referred to the hospital due to generalized hypotonia and a developmental delay after viral infection. Brain MRI revealed bilateral signal abnormalities in the globi pallidi. A muscle biopsy from the right biceps brachii showed no abnormalities. Lactate and pyruvate levels in arterial blood (16.5 mg/dL and 1.48 mg/dL, respectively; normal range: 5–20 mg/dL and 0.3–0.9 mg/dL, respectively) and cerebrospinal liquor (13.5 mg/dL and 1.12 mg/dL, respectively; normal range: 9.1–18.8 mg/dL and 0.26–1.32 mg/dL, respectively) measured once in a non-acute phase were almost normal [6]. At 15 months, she had febrile illness and impaired consciousness with severe metabolic acidosis. Arterial blood ketone bodies, pH, pCO2, and base excess were (8700 μmol/L; normal range: < 130 μmol/L), 7.051, 6.7 mm Hg, and − 26.9 mEq/L, respectively. She required ventilator support and frequent infusions of bicarbonate. A brain MRI showed bilateral signal abnormalities in the globi pallidi and right caudate nucleus (Fig. 1A). Consequently, she developed subarachnoid hemorrhage, had no spontaneous respirations, and demonstrated no pupillary response to light and corneal reflex. At 17 months, electroencephalography (EEG) revealed an absence of brain activity, and auditory brainstem response audiometry showed no response. She used a home mechanical ventilation system until she died at 4 years of age with acute heart failure and severe metabolic acidosis (pH; 6.87, pCO2; 13.5 mm Hg, and base excess; − 29.4 mEq/L).


Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis
Brain MRI of the patients. (A) Brain MRI of patient II-2 at 14 months revealed bilateral signal abnormalities in the globi pallidi and right caudate nucleus. (B) Brain MRI of patient II-4 at 14 months showed bilateral signal abnormalities in the globi pallidi. (C) Brain MRI of patient II-4 at 18 months revealed progression of the pathological lesions, with atrophy of the cortex and enlargement of the ventricles. (D) The brain MRI scan of patient II-4 at 24 months shows improvement in signal abnormalities in the basal ganglia when compared to scans at 14 (B) and 18 (C) months.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121361&req=5

f0005: Brain MRI of the patients. (A) Brain MRI of patient II-2 at 14 months revealed bilateral signal abnormalities in the globi pallidi and right caudate nucleus. (B) Brain MRI of patient II-4 at 14 months showed bilateral signal abnormalities in the globi pallidi. (C) Brain MRI of patient II-4 at 18 months revealed progression of the pathological lesions, with atrophy of the cortex and enlargement of the ventricles. (D) The brain MRI scan of patient II-4 at 24 months shows improvement in signal abnormalities in the basal ganglia when compared to scans at 14 (B) and 18 (C) months.
Mentions: Patient II-2 was the second child of healthy, nonconsanguineous, Japanese parents. She was born at full term gestation after an uncomplicated pregnancy. Her birth weight was 2714 g, and she measured 44 cm (− 2.6 SD) in length, with an occipitofrontal circumference of 32.5 cm (− 0.5 SD). She could hold her head up at 5 months and roll over at 10 months. At 12 months, she was referred to the hospital due to generalized hypotonia and a developmental delay after viral infection. Brain MRI revealed bilateral signal abnormalities in the globi pallidi. A muscle biopsy from the right biceps brachii showed no abnormalities. Lactate and pyruvate levels in arterial blood (16.5 mg/dL and 1.48 mg/dL, respectively; normal range: 5–20 mg/dL and 0.3–0.9 mg/dL, respectively) and cerebrospinal liquor (13.5 mg/dL and 1.12 mg/dL, respectively; normal range: 9.1–18.8 mg/dL and 0.26–1.32 mg/dL, respectively) measured once in a non-acute phase were almost normal [6]. At 15 months, she had febrile illness and impaired consciousness with severe metabolic acidosis. Arterial blood ketone bodies, pH, pCO2, and base excess were (8700 μmol/L; normal range: < 130 μmol/L), 7.051, 6.7 mm Hg, and − 26.9 mEq/L, respectively. She required ventilator support and frequent infusions of bicarbonate. A brain MRI showed bilateral signal abnormalities in the globi pallidi and right caudate nucleus (Fig. 1A). Consequently, she developed subarachnoid hemorrhage, had no spontaneous respirations, and demonstrated no pupillary response to light and corneal reflex. At 17 months, electroencephalography (EEG) revealed an absence of brain activity, and auditory brainstem response audiometry showed no response. She used a home mechanical ventilation system until she died at 4 years of age with acute heart failure and severe metabolic acidosis (pH; 6.87, pCO2; 13.5 mm Hg, and base excess; − 29.4 mEq/L).

View Article: PubMed Central - PubMed

ABSTRACT

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical&ndash;biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C&nbsp;&gt;&nbsp;A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~&nbsp;3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.

No MeSH data available.


Related in: MedlinePlus