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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
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
Inborn 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
The concentration of glutaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
3-Methylglutaric aciduria
MedGen UID:
463302
Concept ID:
C3151952
Finding
An abnormally increased level of 3-hydroxy-3-methylglutaric acid in the urine.
Increased level of 3-hydroxy-3-methylglutaric acid in urine
MedGen UID:
1647053
Concept ID:
C4703617
Finding
The concentration of 3-hydroxy-3-methylglutaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
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.
Elevated urinary 3-methylcrotonylglycine level
MedGen UID:
1782488
Concept ID:
C5539708
Finding
An abnormally increased amount of 3-methylcrotonylglycine in the urine.
Cardiac arrest
MedGen UID:
5456
Concept ID:
C0018790
Finding
An abrupt loss of heart function.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Drowsiness
MedGen UID:
4390
Concept ID:
C0013144
Finding
Abnormal feeling of sleepiness or difficulty staying awake.
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
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
Apathy is a quantitative reduction of motivation and the initiation and persistence of goal-directed behavior, where the accompanying emotions, thoughts, and social interactions are also suppressed.
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.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Excessive daytime somnolence
MedGen UID:
1635612
Concept ID:
C4551761
Sign or Symptom
A state of abnormally strong desire for sleep during the daytime.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
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
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
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.
Hyperuricemia
MedGen UID:
149260
Concept ID:
C0740394
Disease or Syndrome
An abnormally high level of uric acid in the blood.
Decreased circulating carnitine concentration
MedGen UID:
222973
Concept ID:
C1142132
Finding
Concentration of carnitine in the blood circulation below the lower limit of normal.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Elevated serum anion gap
MedGen UID:
1671031
Concept ID:
C4732778
Finding
An abnormally high value of the serum anion gap (the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration).
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Reduced HMG-CoA lyase activity in cultured fibroblasts
MedGen UID:
1053286
Concept ID:
CN376729
Finding
Acitivity of 3-hydroxy-3-methylglutaryl coenzyme A lyase (HMG CoA lyase) below the lower limit of normal in cultured fibroblasts.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
Abnormally pale skin.

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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