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Deficiency of hydroxymethylglutaryl-CoA lyase(HMGCLD)

MedGen UID:
78692
Concept ID:
C0268601
Disease or Syndrome
Synonyms: 3-hydroxy-3-methylglutaric aciduria; 3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase Deficiency; Defect in leucine metabolism; HMG CoA lyase deficiency; HMGCL DEFICIENCY; HMGCLD; Hydroxymethylglutaric aciduria
SNOMED CT: Deficiency of hydroxymethylglutaryl-CoA lyase (124611007); 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (124611007); HMG-CoA lyase deficiency (124611007)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HMGCL (1p36.11)
 
Monarch Initiative: MONDO:0009520
OMIM®: 246450
Orphanet: ORPHA20

Definition

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988). [from OMIM]

Additional description

From MedlinePlus Genetics
3-hydroxy-3-methylglutaryl-CoA lyase deficiency (also known as HMG-CoA lyase deficiency) is an uncommon inherited disorder in which the body cannot process a particular protein building block (amino acid) called leucine. Additionally, the disorder prevents the body from making ketones, which are compounds that are used for energy during periods without food (fasting).

The signs and symptoms of HMG-CoA lyase deficiency usually appear within the first year of life. The condition causes episodes of vomiting, diarrhea, dehydration, extreme tiredness (lethargy), and weak muscle tone (hypotonia). During an episode, blood sugar (glucose) levels can become dangerously low (hypoglycemia), and a buildup of harmful compounds can cause the blood to become too acidic (metabolic acidosis). If untreated, the disorder can lead to breathing problems, convulsions, coma, and death. Episodes are often triggered by an infection, fasting, strenuous exercise, or other types of stress.

HMG-CoA lyase deficiency is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.  https://medlineplus.gov/genetics/condition/3-hydroxy-3-methylglutaryl-coa-lyase-deficiency

Clinical features

From HPO
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
Abnormally pale skin.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
An emotional state of indifference characterized by a lack of interest or concern.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hyperammonemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
An increased concentration of ammonia in the blood.
Organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Glutaric aciduria
MedGen UID:
75695
Concept ID:
C0268594
Disease or Syndrome
An increased concentration of glutaric acid in the urine.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Decreased prothrombin time
MedGen UID:
154375
Concept ID:
C0580413
Finding
Abnormally short time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula
Hyperuricemia
MedGen UID:
149260
Concept ID:
C0740394
Disease or Syndrome
An abnormally high level of uric acid in the blood.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Decreased circulating carnitine concentration
MedGen UID:
222973
Concept ID:
C1142132
Finding
A decreased concentration of carnitine in the blood.
3-Methylglutaric aciduria
MedGen UID:
463302
Concept ID:
C3151952
Finding
An abnormally increased level of 3-hydroxy-3-methylglutaric acid in the urine.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Excessive daytime somnolence
MedGen UID:
1635612
Concept ID:
C4551761
Sign or Symptom
A state of abnormally strong desire for sleep during the daytime.
Increased level of 3-hydroxy-3-methylglutaric acid in urine
MedGen UID:
1647053
Concept ID:
C4703617
Finding
An increase in the level of 3-hydroxy-3-methylglutaric acid in the urine.
Increased level of hippuric acid in urine
MedGen UID:
1640306
Concept ID:
C4703632
Finding
An increase in the level of hippuric acid in the urine.

Professional guidelines

PubMed

Thompson S, Hertzog A, Selvanathan A, Batten K, Lewis K, Nisbet J, Mitchell A, Dalkeith T, Billmore K, Moore F, Tolun AA, Devanapalli B, Bratkovic D, Hilditch C, Rahman Y, Tchan M, Bhattacharya K
Nutrients 2023 Jan 19;15(3) doi: 10.3390/nu15030531. PMID: 36771238Free PMC Article
Huang Z, Liu Y, Huang X, Hu Z, Liu H, Wang L, Liu C, Ren Y
J Mass Spectrom 2019 Feb;54(2):134-140. doi: 10.1002/jms.4314. PMID: 30468550
Mitchell GA, Jakobs C, Gibson KM, Robert MF, Burlina A, Dionisi-Vici C, Dallaire L
Prenat Diagn 1995 Aug;15(8):725-9. doi: 10.1002/pd.1970150807. PMID: 7479590

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022

American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

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