3-Hydroxy-3-Methylglutaryl (or HMG) CoA lyase deficiency is an autosomal recessive genetic disorder that is rarely encountered in clinical practice, although several reports have stressed a rather high prevalence in certain parts of the world such as Saudi Arabia and Portugal [1] [2] [3] [4]. The pathogenesis and the clinical presentation arise from the inability of the affected patients to synthesize ketone bodies, on one hand, (which are one of the primary source of energy during fasting) and degrade one of the essential amino acids leucine [4] [5] [6] [7]. As a result, excessive accumulation of ammonia (hyperammonemia), metabolic acidosis and hypoketotic hypoglycemia develop during the first year of life [3] [4] [5] [8]. These metabolic changes induce symptoms when infants are introduced to dietary protein for the first time, or during prolonged fasting (eg. viral infections) [5] [6]. Nausea, vomiting, lethargy and hypotonia are most important symptoms, whereas respiratory distress and coma are reported in severe cases [4] [6]. Hypoglycemic crises are strikingly similar to severe stages of Reye's syndrome, and can lead to irreversible neurological sequelae (psychomotor retardation, epilepsy), cardiomyopathy, pancreatitis, or even death, as mortality rates are estimated at 20% according to certain reports [1] [5] [6] [7] [9]. For this reason, prompt recognition is vital in preventing complications. Some individuals, on the other hand, in whom the daily diet contains limited amounts of fat and protein, may be completely asymptomatic for a prolonged period of time [5].

• Fatigue

  CASE REPORT A female infant of Pakistani origin was born at 37 weeks gestation via normal delivery following a pregnancy complicated by maternal gestational diabetes, significant morning sickness and fatigue. [scielo.isciii.es]

  These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis. [genico.ch]

• Turkish

  Already 1 h after birth, the female newborn of consanguineous Turkish parents had to be treated because of hypoglycemia (1.5 mmol/l). [ncbi.nlm.nih.gov]

• Intermittent Fever

  During the first week of hospitalization, the patient experienced intermittent fever, averaging two or three episodes per day, with a maximum temperature of 39 C. Seizures occurred one to two times per days with symptoms as described previously. [spandidos-publications.com]

• Recurrent Diarrhea

  The child was formula-fed, and suffered from recurrent diarrhea and was frequently hospitalized, averaging once per month. The boy had a poor appetite and had iron-deficient anemia (hemoglobin, 95–105 g/l; reference, 120–160 g/l). [spandidos-publications.com]

• Cyanosis

  The first patient reported with HMG-CoA lyase deficiency was a boy who presented at 7 months of age with diarrhea and vomiting that were associated with lethargy, pallor, dehydration and events of cyanosis and apnea ( Faull et al 1976a ). [medlink.com]

  His major symptoms included vomiting, cyanosis, apnea, metabolic acidosis, hypoglycemia, and an increase in urine 3-hydroxy-3-methylglutaric acid ( 2 ). To date, 100 cases have been reported worldwide, with an incidence of 3 ). [spandidos-publications.com]

• Spontaneous Rupture of Membranes

  At 36 5/7 weeks, she presented with spontaneous rupture of membranes. Twice maintenance 10{\%} glucose-containing intravenous fluids were initiated. During labor, vomiting and metabolic acidosis developed. Delivery was by cesarean. [jhu.pure.elsevier.com]

  At 36 weeks 5 days, the patient presented with spontaneous rupture of membranes. 10% glucose-containing intravenous fluids at twice maintenance were started immediately. [ncbi.nlm.nih.gov]

• Cesarean Section

  Abhishek Peapally Venugopal, Harish Kashyap Karri, Sreeram Subramanian, Srinivas Murki PRESENTATION A term male infant is born to a consanguineous couple by emergency cesarean section for nonprogressive labor. [neoreviews.aappublications.org]

• Lethargy

  The clinical presentation of an acidotic attack is lethargy, hyperpnoea, tachypnoea and seizures, either at birth (two infants), following first feeding (in five infants), or following vomiting or refusal of food in later infancy. [ncbi.nlm.nih.gov]

  The lack of energy causes seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycemia. Mutations in the HMGCL gene cause HMG-CoA lyase deficiency. [medicalhomeportal.org]

  Occasional attacks with lethargy, pallor, nausea and vomiting occur and are managed by supplementing glucose intake ( Wysocki and Hahnel 1986 ). [medlink.com]

  […] methylglutaryl-CoA lyase deficiency Description 3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive genetic disorder characterized by recurrent episodes of metabolic acidosis, hyperammonemia without ketosis, hypoglycemia, lethargy [genome.jp]

• Foot Drop

  The second woman had residual foot drop and fetal demise from an episode of metabolic decompensation and subsequently chose to terminate her second pregnancy [ Langendonk et al., 2012 ]. [ncbi.nlm.nih.gov]

• Babinski Sign

  The patients muscle tension and knee reflex were weak, and the Babinski sign was negative. No abnormalities in the heart, lungs and abdomen were discerned. [spandidos-publications.com]

The role of a properly obtained patient history (primarily from the parents due to the young age of the patient) is vital in recognizing the typical signs and symptoms of HMG-CoA lyase deficiency. Physicians should inquire about dietary habits, the amount of protein and fat intake on a daily basis, and evaluate if patients were predisposed to metabolic crises by fasting states, such as recent infections or profound physical activity [5] [6]. As soon as clinical criteria suggest a hypoglycemic state, serum glucose levels must be measured, followed by a detailed laboratory workup. Urinalysis (specifically gas chromatography-mass spectrometry, or GC/MS), however, is used as a definite method for recognizing HMG-CoA lyase deficiency, during which detection of organic acids - 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids (leucine metabolites), provides important clues to the diagnosis [1] [6] [10]. Further confirmation can be achieved through more advanced studies that evaluate the enzymatic activity of HMG-CoA lyase and genetic testing. The HMGCL gene, for whom dozens of mutations have been described, is located on chromosome 1 [1] [6].

• Leucine Increased

  Walter et al. 25 showed in a 9 month old infant, that progressive fat restriction (3.1 g/kg/day to 1.7 g/kg/day) lowered urinary excretion of 3-hydroxy-3-methylglutaric acid and 3-methyl-glutaconic acid despite a dietary leucine increase from 50 up to [scielo.isciii.es]

• White Matter Lesions

  Magnetic resonance and computerized tomography brain scans in these infants, however, show white matter lesions and mild atrophy. [ncbi.nlm.nih.gov]

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