Abstract
3-Hydroxy-3-methylglutaryl-coenzyme-A lyase (HMGCL) deficiency, a rare autosomal recessive disorder, is caused by a homozygous or compound heterozygous mutation in the HMGCL gene (chromosome 1p36.11). HMGCL catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Several studies have reported general hepatic findings (e.g., hepatomegaly) in patients with HMGCL deficiency, but currently, there are no available data regarding the incidence and epidemiology of liver involvement. The main objective of our study was to investigate the overall clinical manifestations, laboratory findings, genotype, and presence of hepatic involvement in Saudi patients with HMGCL deficiency. A retrospective chart review of patients with HMGCL deficiency including those with a documented hepatic manifestation was performed at the King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia. We evaluated 50 cases of HMGCL deficiency. Hepatic findings were found in 17 patients at the time of diagnosis. The mean age of hepatic presentation was 135 days, and the median age was 56 days (range: 2–315 days). Hepatomegaly was found in 65%, abnormal biochemical profile in 47%, and an abnormal imaging in 53% of patients. The most frequent mutation in this cohort was the p.Arg41Gln founder mutation (59%). In comparison to data from the current literature, HMGCL deficiency can be considered as a diagnostic metabolite for hepatic manifestations and requires appropriate evaluation, including molecular genetic analysis.
Keywords: HMGCL deficiency, hepatic manifestations, hepatomegaly, mutation, Saudi Arabia
Introduction
3-Hydroxy-3-methylglutaryl-coenzyme-A lyase (HMGCL) deficiency (OMIM #246450), an inborn error of ketone body synthesis and leucine metabolism, is a rare autosomal recessive disease. The mitochondrial enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the conversion of HMG-CoA to acetoacetate and acetyl-coenzyme A. This reaction is the final step of ketogenesis from fatty acids, and leucine degradation, thus, HMGCL deficiency can also be considered an organic acidemia. Patients with this disease are prone to have severe metabolic decompensations with hypoketotic hypoglycemia and metabolic acidosis, which often occur within the neonatal period and may result in permanent neurological damage or death, if not treated immediately. 1 2 3 4 5 6 In the literature, there is only a few reports that have provided a comprehensive clinical overview on large groups of patients. 7 8 9 10 11 12
A diagnosis of a hepatic manifestation of HMGCL deficiency includes the following: hepatomegaly, an abnormal liver biochemical profile, fatty liver, and hepatic steatosis by liver biopsy, 13 14 and also may be associated with nonketotic hypoglycemia and hyperammonemia. It can present with Reye-like syndrome in the form of recurrent hypoglycemia and liver function derangement. 15 16 17 18 19 Another gastrointestinal nonhepatic finding is acute or recurrent pancreatitis. The hepatic involvement usually improves after protein and diet restriction. 20 21 Anticipation of HMGCL deficiency in early age and starting the appropriate diet leads to good prognosis in term of systemic symptoms, including the liver. 22 To date, there are no studies describing the genotype–phenotype correlation in patients with this disease in regard to the liver-related findings in details. One report described elevated transaminase activities, which were documented in 14 out of 20 patients with HMGCL deficiency during the initial decompensation. The median age of a general manifestation was 56 days, but hepatic manifestation median age was not stated in that study. 5 There have been previous reports of Saudi patients with HMGCL deficiency documenting clinical and molecular genetic results but did not focus on hepatic involvement in this disease. 9 23
HMGCL deficiency is reported to be common in Saudi Arabia due to the high rate of consanguinity throughout the kingdom. 9 23 The main aims of this study were to investigate the epidemiology of the clinical manifestations, laboratory and genetic findings of Saudi patients having hepatic involvement with HMGCL deficiency.
Patients and Methods
We retrospectively reviewed our database for cases of HMGCL deficiency that presented from 1990 until 2015 at our clinics at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia. Data of clinical, biochemical, imaging, and molecular genetic characteristics were collected by a systematic chart review. This retrospective review was approved and adhered to institutional guidelines (RAC# 2151199) and to the tenets of Declaration of Helsinki. The definition of a hepatic manifestation of HMGCL deficiency was met if a patient had one or more of the following findings documented: hepatomegaly, an abnormal biochemical profile, an abnormal imaging, and/or histopathological changes. Abdominal ultrasound examination showing normal liver, fatty liver, and liver with gallstones was assessed as shown in Fig. 1 . Two main primary outcomes were studied: (1) the incidence of clinical, biochemical, and imaging findings and (2) genotype and phenotype correlation with hepatic involvement.
Fig. 1.
Abdominal U/S examination/U/S of liver (three patients with HMGCL deficiency) showing normal liver, fatty liver, and liver with gallstones. ( A ) U/S of liver = normal: the visualized parts of the liver are homogeneous without suspicious lesions or echogenicity. ( B ) Fatty liver: 18-year-old man, the liver is normal in size with increased parenchymal echogenicity in keeping with fatty infiltration, no focal lesions. ( C ) U/S of liver shows gallstones: 19-year-old woman, the liver demonstrates homogeneous echotexture with no suspicious focal hepatic lesions. No biliary dilatation. There are multiple gallstones, no signs of cholecystitis. HMGCL, 3-hydroxy-3-methylglutaryl-coenzyme-A lyase; U/S, ultrasound.
Results
During the study period, 50 cases of HMGCL deficiency were referred to our center for further evaluation and management. In total, 17 patients were documented to have hepatic manifestations during the initial presentation with a mean age of 135 days, and median age was 56 days (range: 2–315 days). Details of the study cohort are described in detail in Table 1 . Consanguinity was present in all patients. The majority of patients with hepatic manifestations showed a Reye-like syndrome picture: hepatomegaly (11/17, 65%), 9/17, 53% of the patients with hepatomegaly showed fatty liver by ultrasound ( Fig. 1 ). Eight out of 17 (47%) patients had high transaminase during the initial decompensation; seven of them were associated with hypoglycemia and six with hepatomegaly.
Table 1. Characteristics of HMGCL deficiency in 17 Saudi patients with hepatic manifestations.
| Demographic and clinical data at presentation | Hepatobiliary finding | Outcome | Diagnostic tests | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age (d) | Gender (F, M) | Region | Hypoglycemia | Acidosis | Seizure | Hypocalcemia | Coma | Hepatomegaly | High transaminase | Fatty liver by US | Performed liver biopsy | Multiple gallstones by US | Last follow-up age (y) | Epilepsy | White matter changes by brain MRI | Abnormal EEG | Learning disability | ADHD | Short stature | Positive tandem mass spectrometry | Positive organic acid | Molecular genotype |
| 2 | F | North | + | + | − | − | − | − | + | + | − | − | 14 | − | + | + | + | + | − | + | + | c.206_207delCT (p.Ser69Cysfs*11) |
| 48 | M | Central | − | − | − | − | − | − | + | − | − | − | 15 | + | − | + | − | − | − | + | + | NA |
| 7 | M | Central | + | + | + | + | − | + | − | + | − | − | 19 | + | − | + | − | − | − | + | + | c.122G > A (p.Arg41Gln) |
| 168 | F | Central | + | + | − | − | − | − | − | + | − | + | 21 | − | + | − | + | − | − | + | + | c.122G > A (p.Arg41Gln) |
| 280 | M | Central | + | + | − | − | + | + | − | − | − | − | 17 | − | − | − | − | − | − | − | + | c.122G > A (p.Arg41Gln) |
| 252 | M | South | + | + | − | − | − | + | + | − | − | − | 21 | + | − | − | − | − | − | + | + | c.206_207delCT (p.Ser69Cysfs*11) |
| 56 | F | Central | − | + | − | − | − | + | − | + | − | − | 28 | + | + | − | − | − | − | + | + | NA |
| 308 | F | Central | + | + | − | − | − | + | + | + | − | − | 19 | − | − | − | − | − | − | + | + | NA |
| 224 | F | Eastern | − | + | − | + | − | + | − | − | − | + | 21 | + | + | − | + | − | − | + | + | c.914_915delTT (p.Phe305Tyrfs*10) |
| 315 | M | Central | + | + | + | − | + | + | − | − | − | − | 23 | + | + | − | − | − | − | + | + | c.122G > A (p.Arg41Gln) |
| 56 | F | Central | − | + | − | − | − | − | − | − | − | − | 16 | − | − | − | + | + | − | + | + | NA |
| 168 | F | Central | + | + | − | − | + | + | + | − | − | − | 13 | + | − | − | − | − | + | + | + | c.122G > A (p.Arg41Gln) |
| 14 | M | Western | + | + | − | − | − | + | + | − | − | − | 10 | + | − | + | + | − | − | + | + | c.122G > A (p.Arg41Gln) |
| 49 | M | Central | + | + | − | − | − | + | + | + | − | − | 13 | − | − | − | + | + | + | + | + | c.122G > A (p.Arg41Gln) |
| 21 | M | South | − | − | − | − | − | − | − | + | − | + | 7 | − | − | − | − | − | − | + | + | c.122G > A (p.Arg41Gln) |
| 56 | F | Central | − | + | − | − | − | − | − | + | − | − | 19 | + | − | − | + | − | − | + | + | c.122G > A (p.Arg41Gln) |
| 280 | F | Central | + | + | − | − | − | + | + | + | + | − | 22 | − | − | − | − | − | − | + | + | c.122G > A (p.Arg41Gln) |
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; EEG, electroencephalogram; F, female; HMGCL, 3-hydroxy-3-methylglutaryl-coenzyme-A lyase; M, male; MRI, magnetic resonance imaging; NA, not available; US, ultrasound.
Upon the analysis, we found 3/8 values of alanine transaminase (ALT) and 2/8 values of aspartate transaminase (AST). For (ALT), the median activity was 285 U/L, and the mean activity was 244 U/L (range: 56–392). For (AST), the median activity was 456 U/L, and the mean activity was 456 U/L (range: 87–825). We could not find any result for gamma-glutamyltransferase from the analysis. None of hepatic patients was documented to have developed hyperbilirubinemia, coagulopathy, or hyperammonemia upon chart review. Acidosis at first presentation was documented in 88% (15/17). One patient had high levels of liver enzyme with acidosis, and two patients presented with acidosis in conjunction with fatty liver changes as observed by ultrasound.
Initially, all of the 17 patients with hepatomegaly were biochemically confirmed by urine organic acid analysis (high 3-hydroxy-3-methylglutaric acid). Tandem mass spectrometry (TMS) was positive (high C5-OH acylcarnitine) for 16 of the patients. Some patients were diagnosed with HMGCL deficiency by the National Newborn Screening Program/KFSH&RC. All of these subgroups have been kept on early proper management and have not developed any major systemic complications, including those of the hepatic system.
The genetic test results of all patients in this cohort showed that 10/17 patients were found to be homozygous for the founder c.122G > A (p.Arg41Gln) mutation. 23 They predominantly originated from the central region of Saudi Arabia (9/10). Another two 2 bp deletion mutations (c.914_915delTT; p.Phe305Tyrfs*10 and c.206_207delCT; p.Ser69Cysfs*11) 24 25 were found in three additional patients. No mutation was identified in the remaining four patients ( Table 1 ).
Interestingly, there was one female patient who underwent liver biopsy, and her results showed diffused fatty changes. She developed a picture of gastroenteritis, acidosis, hepatomegaly, and high liver enzymes at the age of 10 months. In addition, she had high levels of cholesterol, triglycerides, and uric acid. Based on these clinical descriptions, the glycogen storage disease type 1 was suspected. Ultrasound results showed fatty liver, and further biopsy revealed a picture of steatosis. The liver biopsy was performed in another hospital previously, but corresponding images were not available during our data collection. After a subsequent referral to our hospital, TMS and urine organic acid analysis established a diagnosis of HMGCL deficiency that was later confirmed by molecular genetic analysis which revealed a homozygous common c.122G > A (p.Arg41Gln) mutation.
We found that 3/50 of our HMGCL deficiency patients (two females and one male) had gallstones ( Fig. 1 ). One of these (a female) had hepatomegaly with normal liver enzyme and normal liver parenchyma by ultrasound. Mutation analysis of HMGCL revealed a homozygous c.914_915delTT (p.Phe305Tyrfs*10) mutation. The other two patients (one female and one male) had gallstones without any hepatic involvement, and they were both homozygous for c.122G > A (p.Arg41Gln) mutation in HMGCL . The female patient also had a gallbladder polyp, which was discovered accidentally by ultrasound associated with fatty liver but did not have any gallstones.
Another female patient developed pancreatitis with one of her crises, but she did not have any liver involvement. She was homozygous for c.914_915 delTT mutation (p.Phe305Tyrfs*10), a known mutation that was reported previously in patients with acute pancreatitis in association with HMGCL deficiency. 26
We investigated neurological association as a major feature of HMGCL deficiency in our cohort and found that a total of 9/17 patients developed epilepsy; 1 with elevated transaminase, 1 with fatty liver, 4 with hepatomegaly, and 3 with hepatomegaly plus elevated transaminase. Out of the nine patients with reported epilepsy, five patients were homozygous for the p.Arg41Gln, one homozygous for p.Phe305Tyrfs*10, one homozygous for p.Ser69Cysfs*11, and in two patients, the mutation was not determined.
Interestingly, during follow-up, we found that the clinical and biochemical hepatic parameters have been normalized by a strict diet management (low protein, especially leucine) plus a carnitine supplement.
Discussion
To our knowledge, our data are the first study that describes different characteristics of hepatic involvement of HMGCL deficiency in detail and in a large sample cohort compared with other case reports. We have performed an extensive literature review for previous case reports of patients with HMGCL deficiency including hepatic manifestations ( Table 2 ). In concurrence with other reports, most of the previously reported presentations were Reye-like syndrome, which was observed in our study. We have three patients with hepatic manifestations but without metabolic acidosis. Two patients from a previous report 5 were diagnosed due to recurrent vomiting and elevated transaminase activities without metabolic decompensation, which indicates that HMGCL deficiency may also present with mild chronic hepatic symptoms. Therefore, it is important to consider this disorder for patients who have hepatic involvement even without a metabolic dysfunction element. To date, there are no reports indicating association between gallbladder abnormalities and HMGCL deficiency. The data from this cohort have showed 3 patients out of 50 with abnormal gallbladder findings, thus suggesting a possible correlation between HMGCL deficiency and gallbladder or biliary system. For extrahepatic manifestations, our findings were similar to other reports, especially those concerning neurological symptoms.
Table 2. Literature review for patients with HMGCL deficiency and general hepatic findings.
| Literature information | Clinical description at initial presentation | Method of diagnosis | Management and outcome | Molecular genetics |
|---|---|---|---|---|
| Case report: Robinson et al (1980) 15 | -2-year-old male -Fever -Reye-like syndrome -Hepatomegaly -Elevated transaminases -Hypoglycemia -Acidosis -Liver pathology: steatosis |
-Urine organic acid -Enzymatic assay of the skin fibroblast and liver |
-Long-term management was not mentioned -Excellent outcome |
Not done |
| Case report: Dasouki et al (1987) 22 | -3-day-old female -Coma -Hypothermia - Hepatomegaly -Elevated transaminases -Nonketotic hypoglycemia -Acidosis |
-Urine organic acid | -Protein and fat restriction -Carnitine -Excellent outcome |
Not done |
| Case report: Plöchl et al (1990) 20 | -1-year-old female -Recurrent dehydration -Hepatomegaly -Elevated transaminases -Acidosis -Hypoglycemia |
-Urine organic acid -Enzymatic assay of the skin fibroblast |
-Protein and fat restriction -Carnitine -Excellent outcome |
Not done |
| Case report: Karcher et al (1993) 18 | -3-year-old girl -Reye-like syndrome |
-Urine organic acid -Enzymatic assay of the skin fibroblast and liver |
-Protein and fat restriction | Not done |
| Case report: Eirís et al (1998) 16 | -10-month-old female -Apnea and coma -Reye-like syndrome -Hepatomegaly -Nonketotic hypoglycemia -Elevated transaminases -Acidosis -Hyperammonemia |
-Enzymatic essay of skin fibroblast | Not available | Not done |
| Case report: Lee et al (1999) 19 | -Reye-like syndrome -Hepatomegaly -Elevated transaminases -Acidosis -Hyperammonemia -Convulsions |
-Urine organic acid -Analysis of free carnitine and acylcarnitines |
Not available | Not done |
| Case report: Urgançi et al (2001) 14 | -7-month-old female -Abdominal distension -Fever -Hepatomegaly -Elevated transaminases -Splenomegaly -Acidosis -Hyperammonemia -Hypoglycemia -Liver pathology: steatosis |
-Urine organic acid -Enzymatic assay of the skin fibroblast and liver |
-Protein and fat restriction -Carnitine -Excellent outcome |
Not done |
| Case Series: Grünert et al (2017) 5 | -37 patients -14 patients with hepatomegaly -13 patients with elevated transaminase -Epilepsy -Reye-like syndrome Hypoglycemia -Acidosis -Hyperammonemia |
-Newborn screening (some patients) -Urine organic acid |
-Protein and fat restriction -Carnitine -49% of the total with cognitive impairment -Outcome of the patients with liver disease is not stated |
-
HMGCL
gene screening
-7 novel mutations reported |
Abbreviation: HMGCL, 3-hydroxy-3-methylglutaryl-coenzyme-A lyase.
The presence of consanguinity was not highlighted in the majority of previous studies except in one multicenter study, and the consanguinity was documented to be 50%. 5 In our cohort, consanguinity is a striking feature (100%). However, it must be noted that the high level of consanguinity is comparable to that among patients who have been reported with other metabolic disorders in Saudi Arabia. 27
Biochemical confirmation of HMGCL deficiency was done by urine organic analysis for all of our patients and 94% of TMS suggested the initial diagnosis. We do not recommend enzymatic essay from skin fibroblast culture or liver tissue, as the metabolic screening is consistent with the biochemical diagnosis. Regarding the diagnosis of hepatic elements, previous four studies have reported steatosis by liver biopsy that was done as a part of work-up for chronic hepatitis because of an unreached diagnosis. 13 15 16 28 Abdomen ultrasound shows fatty liver appearance in our data (53%), which indicates the lack of necessity to proceed with an invasive procedure. Screening of this disease has been added to the National Newborn Screening Program, launched in 2005, but unfortunately, not all hospitals in Saudi Arabia are covered by this service. Currently, there are screening programs underway to cover all regions to avoid the treatable complications by an early diagnosis. Further future preventative measures, such as carrier testing, prenatal and preimplantation genetic diagnoses for a family with affected children, are also highly recommended. In addition, an excellent outcome was found with regard to liver-related symptoms as well as extrahepatic symptoms, such as neurological involvement after restricting protein (leucine) and after providing a carnitine supplement. An early diagnosis is critical to start the recommended management as soon as possible.
Mutation analysis confirms that the most common and founder mutation in Saudi patients with HMGCL deficiency is p.Arg41Gln. 23 24 Most of the homozygous patients for this missense mutation are originated from the central region, which directly correlates with the incidence of the disease in this particular region. Therefore, future targeting of a specific mutation with the observed correlated Saudi region could be considered for a rapid molecular analysis. Finally, from our observations, we found that there is no specific genotype–phenotype correlation in regard to the presence of hepatic manifestations ( Table 1 ).
In conclusion, the hepatic involvement with HMGCL deficiency is not a negligible feature and should be considered with any patient manifesting Reye-like syndrome picture (hypoketotic hypoglycemia with hepatomegaly or liver function derangement). A complete liver work-up should be performed for any patient suspected to have HMGCL deficiency, except for a liver biopsy, which is not required. We recommend considering the diagnosis of HMGCL deficiency for any patient with any hepatic features presenting at an early age that have been reviewed in our study or if Reye's syndrome symptoms are present. Starting the appropriate diet early is crucial for improving the course of the disease including hepatic involvement. Hepatic manifestations of HMGCL deficiency are not rare in Saudi patients affected by this disease. Awareness about HMGCL deficiency presenting with hepatic findings is beneficial for those who are directly involved in diagnosis, treatment, and management of patients with this disease to hopefully avoid preventable complications.
Funding Statement
Funding This project was funded by King Faisal Specialist Hospital & Research Centre (RAC # 2151199).
Footnotes
Conflict of Interest None declared.
References
- 1.Mitchell G F, Fukao T. New York: McGraw-Hill; 2001. Inborn errors of ketone body metabolism. [Google Scholar]
- 2.Sass J O. Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis. 2012;35(01):23–28. doi: 10.1007/s10545-011-9324-6. [DOI] [PubMed] [Google Scholar]
- 3.Matern D. Berlin: Springer; 2008. Acylcarnitines, including in vitro loading tests; pp. 171–206. [Google Scholar]
- 4.Jörn Oliver Sass J G. Berlin, Heidelberg: Springer-Verlag; 2014. Disorders of ketone body metabolism. [Google Scholar]
- 5.Grünert S C, Schlatter S M, Schmitt R N. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients. Mol Genet Metab. 2017;121(03):206–215. doi: 10.1016/j.ymgme.2017.05.014. [DOI] [PubMed] [Google Scholar]
- 6.Yilmaz O, Kitchen S, Pinto A. [3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review] Nutr Hosp. 2018;35(01):237–244. doi: 10.20960/nh.1329. [DOI] [PubMed] [Google Scholar]
- 7.Cardoso M L, Rodrigues M R, Leão E. The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. Mol Genet Metab. 2004;82(04):334–338. doi: 10.1016/j.ymgme.2004.06.003. [DOI] [PubMed] [Google Scholar]
- 8.Gibson K M, Breuer J, Nyhan W L. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr. 1988;148(03):180–186. doi: 10.1007/BF00441397. [DOI] [PubMed] [Google Scholar]
- 9.Ozand P T, al Aqeel A, Gascon G, Brismar J, Thomas E, Gleispach H. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia. J Inherit Metab Dis. 1991;14(02):174–188. doi: 10.1007/BF01800590. [DOI] [PubMed] [Google Scholar]
- 10.Pié J, López-Viñas E, Puisac B. Molecular genetics of HMG-CoA lyase deficiency. Mol Genet Metab. 2007;92(03):198–209. doi: 10.1016/j.ymgme.2007.06.020. [DOI] [PubMed] [Google Scholar]
- 11.Menao S, López-Viñas E, Mir C. Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria. Hum Mutat. 2009;30(03):E520–E529. doi: 10.1002/humu.20966. [DOI] [PubMed] [Google Scholar]
- 12.Vargas C R, Sitta A, Schmitt G. Incidence of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HL) deficiency in Brazil, South America. J Inherit Metab Dis. 2008;31 03:511–515. doi: 10.1007/s10545-007-0756-y. [DOI] [PubMed] [Google Scholar]
- 13.Gibson K M, Breuer J, Kaiser K. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients. J Inherit Metab Dis. 1988;11(01):76–87. doi: 10.1007/BF01800058. [DOI] [PubMed] [Google Scholar]
- 14.Urgançi N, Arapoğlu M, Evrüke M, Aydin A. A rare cause of hepatomegaly: 3-hydroxy-3-methylglutaryl coenzyme-a lyase deficiency. J Pediatr Gastroenterol Nutr. 2001;33(03):339–341. doi: 10.1097/00005176-200109000-00022. [DOI] [PubMed] [Google Scholar]
- 15.Robinson B H, Oei J, Sherwood W G, Slyper A H, Heininger J, Mamer O A.Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome Neurology 198030(7 Pt 1):714–718. [DOI] [PubMed] [Google Scholar]
- 16.Eirís J, Ribes A, Fernández-Prieto R, Rodríguez-García J, Rodríguez-Segade S, Castro-Gago M. [3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome] Rev Neurol. 1998;26(154):911–914. [PubMed] [Google Scholar]
- 17.Leonard J V, Seakins J W, Griffin N K.beta-Hydroxy-beta-methyglutaricaciduria presenting as Reye's syndrome Lancet 19791(8117):680. [DOI] [PubMed] [Google Scholar]
- 18.Karcher C, Rousselot J M, Lefebvre E, Vidailhet M. [Hydroxy-methyl-glutaryl-coenzyme A lyase deficiency manifesting as Reye's syndrome in a 3-year-old girl] Pediatrie. 1993;48(05):385–387. [PubMed] [Google Scholar]
- 19.Lee C, Tsai F J, Wu J Y. 3-hydroxy-3-methylglutaric aciduria presenting with Reye like syndrome: report of one case. Acta Paediatr Taiwan. 1999;40(06):445–447. [PubMed] [Google Scholar]
- 20.Plöchl E, Bachmann C, Colombo J P, Gibson K M. [3-hydroxy-3-methylglutaraturia. Clinical aspects, follow-up and therapy in a young child] Klin Padiatr. 1990;202(02):76–80. doi: 10.1055/s-2007-1025492. [DOI] [PubMed] [Google Scholar]
- 21.Muñoz-Bonet J I, Ortega-Sánchez M D, León Guijarro J L. Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Ital J Pediatr. 2017;43(01):12. doi: 10.1186/s13052-017-0333-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Dasouki M, Buchanan D, Mercer N, Gibson K M, Thoene J. 3-Hydroxy-3-methylglutaric aciduria: response to carnitine therapy and fat and leucine restriction. J Inherit Metab Dis. 1987;10(02):142–146. doi: 10.1007/BF01800039. [DOI] [PubMed] [Google Scholar]
- 23.Al-Sayed M, Imtiaz F, Alsmadi O A, Rashed M S, Meyer B F. Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC Med Genet. 2006;7:86. doi: 10.1186/1471-2350-7-86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Mitchell G A, Ozand P T, Robert M F. HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am J Hum Genet. 1998;62(02):295–300. doi: 10.1086/301730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Mitchell G A, Robert M F, Hruz P W. 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J Biol Chem. 1993;268(06):4376–4381. [PubMed] [Google Scholar]
- 26.Wilson W G, Cass M B, Søvik O, Gibson K M, Sweetman L. A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Eur J Pediatr. 1984;142(04):289–291. doi: 10.1007/BF00540255. [DOI] [PubMed] [Google Scholar]
- 27.Al Bu Ali W H, Balaha M H, Al Moghannum M S, Hashim I. Risk factors and birth prevalence of birth defects and inborn errors of metabolism in Al Ahsa, Saudi Arabia. Pan Afr Med J. 2011;8:14. doi: 10.4314/pamj.v8i1.71064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Gibson K M, Lee C F, Kamali V. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency as detected by radiochemical assay in cell extracts by thin-layer chromatography, and identification of three new cases. Clin Chem. 1990;36(02):297–303. [PubMed] [Google Scholar]