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HMG-CoA Lyase Deficiency

3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

HMG-CoA lyase deficiency is a rare genetic disorder characterized by the deficiency of an enzyme that is necessary for the synthesis of ketone bodies and metabolism of leucine, an essential amino acid. Thus, patients present with severe and potentially life-threatening hypoglycemia, metabolic acidosis without ketosis, hyperammonemia, and even coma when introduced to dietary protein. The diagnosis may be difficult to attain, which is why a comprehensive workup is vital.


Presentation

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]
Weight Gain
  • Maintenance of strict metabolic control through adequate nutrition and monitoring of maternal and fetal weight gain was employed.[ncbi.nlm.nih.gov]
  • Poor feeding, poor weight gain, vomiting and diarrhea, lethargy, and hypotonia are initial symptoms.[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]
Nausea
  • Six weeks later, the patient continued to have nausea and also complained of intermittent vomiting attributed to early pregnancy.[ncbi.nlm.nih.gov]
  • The 19-year-old patient was admitted because of recurrent vomiting and nausea. Diagnostics revealed pregnancy at week 8 of gestation. Metabolic analyses revealed normal lactate and blood glucose levels and normal acid-base status.[doi.org]
  • Nausea, vomiting, lethargy and hypotonia are most important symptoms, whereas respiratory distress and coma are reported in severe cases.[symptoma.com]
  • Occasional attacks with lethargy, pallor, nausea and vomiting occur and are managed by supplementing glucose intake ( Wysocki and Hahnel 1986 ).[medlink.com]
Recurrent Vomiting
  • The 19-year-old patient was admitted because of recurrent vomiting and nausea. Diagnostics revealed pregnancy at week 8 of gestation. Metabolic analyses revealed normal lactate and blood glucose levels and normal acid-base status.[doi.org]
  • Table I Fasting tolerance test result for case study at the age of 10 months By 11 months of age she had required 11 hospitalizations, presenting mainly with recurrent vomiting, metabolic acidosis and hyperammonaemia without obvious contributing factors[scielo.isciii.es]
  • The picture of methymalonic acidemia as recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, and lethargy that can lead to coma and death is often seen in the first week of life. Metabolic acidosis is pronounced.[genico.ch]
Failure to Thrive
  • Initial signs/symptoms may include: Poor feeding Vomiting Irritability Lethargy Lab findings: Metabolic acidosis Non-ketotic hypoglycemia If not treated promptly and consistently, patients may experience: Failure to thrive Hepatomegaly Seizures Apnea[medicalhomeportal.org]
  • Failure to thrive, vomiting, and hypoglycemia may be seen.[genico.ch]
Episodic Vomiting
  • Symptoms are progressive spastic paraplegia, failure to thrive, delayed milestones, hyperactivity and irritability, with episodic vomiting, hyperammonemia and seizures. Mental retardation is a result of cerebral atrophy which leads to microcephaly.[genico.ch]
Tachycardia
  • At 12 hr after delivery she developed tachycardia and hypertension in the setting of anemia due to intrapartum blood loss and volume-overload secondary to aggressive fluid support. Hypertension improved with administration of nifedipine.[ncbi.nlm.nih.gov]
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]
Psychomotor Retardation
  • 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%[symptoma.com]
  • Psychomotor retardation is a life-long complication. Some patients have first presented later in infancy with encephalopathy and associated ketoacidosis, or developmental delay.[genico.ch]
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 disease is characterized by recurrent episodes of metabolic acidosis, hyperammonemia without ketosis, hypoglycemia, lethargy, hepatomegaly, and seizures.[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]
  • Nausea, vomiting, lethargy and hypotonia are most important symptoms, whereas respiratory distress and coma are reported in severe cases.[symptoma.com]
  • Occasional attacks with lethargy, pallor, nausea and vomiting occur and are managed by supplementing glucose intake ( Wysocki and Hahnel 1986 ).[medlink.com]
Learning Difficulties
  • In contrast, lack of compliance, which was also due to learning difficulties, promoted metabolic decompensations and eventually led to fatal decompensation in the case described above (Langendonk et al. 2012 ).[ncbi.nlm.nih.gov]
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]

Workup

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]

Treatment
  • […] intravenous glucose treatment and finally led to the diagnosis.[ncbi.nlm.nih.gov]
  • With metabolic monitoring and treatment as before no decompensation occurred. At week 38 of gestation, she delivered a healthy female infant by elective Caesarian section (Apgar 9/10/10).[doi.org]
  • Provide emergency treatment/referral for symptoms hypoglycemia, metabolic acidosis, or seizures.[medicalhomeportal.org]
  • Many babies are screened at birth so that treatment may begin early, however the conditions included in newborn screening vary state by state. For more information, visit Baby’s First Test. Talk with your doctor about the most current treatments.[diseaseinfosearch.org]
  • It is possible, even with treatment, for babies with 3-hydroxy-3-methylglutaric aciduria (HMG) to have low blood sugar and other signs of HMG. Early screening and treatment are very important.[babysfirsttest.org]

Prognosis
  • However, with effective treatment available, prognosis is favorable and majority of symptoms can be avoided. The disease severity cannot be predicted based on the inherited variants.[sema4genomics.com]
  • The prognosis of MSUD is guarded, although early intervention may lead to a better prognosis.[pediatricneuro.com]
  • With prompt diagnosis, prognosis of HMG-CoA lyase deficiency is good (Gibson et al. 1988 ). Today, an increasing number of patients reach adulthood.[ncbi.nlm.nih.gov]
  • Prognosis Prognosis is guarded. Although intellectual impairment is the rule, even among patients who receive excellent and timely treatment, some patients with ASA lyase deficiency reportedly develop normally.[emedicine.medscape.com]
  • At the last follow-up, six month after initial hospitalization (age, 26 months), the patient remained unresponsive to calling and his prognosis was poor.[spandidos-publications.com]

Etiology
  • The etiology in 70 to 80% of the non-familial cases is unknown.[genico.ch]

Epidemiology
  • Epidemiology [ edit ] Less than 20 patients with MGA type I have been reported in the literature (Mol Genet Metab. 2011 Nov;104(3):410-3. Epub 2011 Jul 26.)[en.wikipedia.org]
  • Epidemiology Frequency United States ASA lyase deficiency is rare,, affecting an estimated 1 in 70,000 live births.[emedicine.medscape.com]
  • Am J Hum Genet 75:97–105 PubMedCentral PubMed CrossRef Google Scholar Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF (2004) The epidemiology of mitochondrial disorders – past, present and future.[link.springer.com]
  • Population and epidemiology information point to G6PD deficiency as providing some resistance to malaria. Clinical Babies with G6PD deficiency appear normal at birth.[genico.ch]
Sex distribution
Age distribution

Pathophysiology
  • PubMed abstract / Full Text The pathophysiology of 3-Hydroxy-3-methylglutaric aciduria, caused by HMG-CoA lyase deficiency, is only partially understood.[medicalhomeportal.org]
  • Pierozan P, Martell RW, Lagranha VL, Busanello EN and Leipnitz G: In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: A potential pathophysiological[spandidos-publications.com]
  • Pathophysiology The hepatic urea cycle is the major route for waste nitrogen disposal; nitrogen generation results chiefly from protein and amino acid metabolism.[emedicine.medscape.com]
  • 149(5):346-50. [ Links ] 14. da Rosa MS, Seminotti B, Ribeiro CAJ, Parmeggiani B, Grings M, Wajner M, et al. 3-Hydroxy-3-methylglutaric and 3-methylglutaric acids impair redox status and energy production and transfer in rat heart: relevance for the pathophysiology[scielo.isciii.es]
  • The pathophysiology and molecular biology vary among different forms of SCID, however, the lack of T-cell and B-cell function is the common endpoint in all forms of SCID.[genico.ch]

Prevention
  • Intravenous 10{\%} glucose-containing fluids should be provided to prevent catabolism and metabolic decompensation during labor and delivery.[jhu.pure.elsevier.com]
  • 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.[symptoma.com]
  • […] names HMG-CoA lyase deficiency or Hydroxymethylglutaric aciduria HMG-CoA 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is an uncommon inherited disorder in which the body cannot properly process the amino acid leucine. [1] Additionally, the disorder prevents[en.wikipedia.org]
  • Additionally, the disorder prevents the body from making ketones, which are used for energy during fasting. Additional recommended knowledge Presentation This disorder usually appears within the first year of life.[chemie.de]
  • Intravenous 10% glucose-containing fluids should be provided to prevent catabolism during labor and delivery and postpartum period.[ncbi.nlm.nih.gov]

References

Article

  1. Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF. Mutations underlying 3-Hydroxy-3-Methylglutaryl CoA Lyase deficiency in the Saudi population. BMC Med Genet. 2006;7:86.
  2. Ozand PT DEB, Gascon GG. Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol. 1992;7 Suppl: S4–11.
  3. Muroi J YT, Uematsu A, Shigematsu Y, et al. Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. Hum Genet. 2000;107:320–326.
  4. Cardoso ML, Rodrigues MR, Leão E, et al. The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. Mol Genet Metab. 2004;82:334–338.
  5. Wysocki SJ HR. 3-Hydroxy-3-methylglutaryl-coenzyme a lyase deficiency: a review. J Inherit Metab Dis. 1986;9:225–233.
  6. Muñoz-Bonet JI, Ortega-Sánchez M del C, León Guijarro JL. Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Ital J Pediatr. 2017;43:12.
  7. Leung AAC, Chan AK, Ezekowitz JA, Leung AKC. A Case of Dilated Cardiomyopathy Associated with 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG CoA) Lyase Deficiency. Case Rep Med. 2009;2009:183125.
  8. Ashmarina LI PAV., Branda SS, Isaya G, Mitchell GA. 3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and processing in peroxisomes and mitochondria. J Lipid Res. 1999;40:70–75.
  9. Santarelli F, Cassanello M, Enea A, et al. A neonatal case of 3-hydroxy-3-methylglutaric-coenzyme A lyase deficiency. Ital J Pediatr. 2013;39:33.
  10. Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr. 1988;148(3):180-186.

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Last updated: 2019-07-11 20:40