Systemic primary carnitine deficiency disease (SPCD)

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: SLC22A5 (HGNC:10969)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 05/02/2022
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
SLC22A5	systemic primary carnitine deficiency disease (0008919)	212140	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric. The group notes the paucity of data regarding symptomatic presentation in adulthood; most of these data are extrapolated from symptomatic presentation in the pediatric population.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from carnitine deficiency / Evaluation by a specialist to guide treatment with levocarnitine supplementation and an illness management protocol	1	2D	3C	3	9DC

Severity of Outcome

Prevalence of the Genetic Condition

Systemic primary carnitine deficiency (CDSP) exact prevalence is unknown and varies depending on the population. Excluding isolated populations, prevalence estimates range from 1:20,000 to 1:120,000. Since some individuals with CDSP may remain asymptomatic throughout their entire life, the prevalence of CDSP in the general population may be much higher than originally anticipated.

Clinical Features (Signs / symptoms)

The clinical manifestations of systemic primary carnitine deficiency (CDSP) can vary widely with respect to age of onset, organ involvement, and severity of symptoms. The CDSP phenotype encompasses a broad clinical spectrum including infantile metabolic (hepatic) presentation, childhood myopathic (cardiac) presentation, fatigability in adulthood, or absence of symptoms. Episodes of metabolic decompensation in children are characterized by poor feeding, irritability, lethargy, hepatic encephalopathy, hepatomegaly, and/or coma. Laboratory evaluations usually reveal hypoketotic hypoglycemia, hyperammonemia, and elevated liver transaminases. Myopathic manifestations include, hypotonia, skeletal muscle weakness, elevated serum creatine kinase (CK), and dilated cardiomyopathy leading to heart failure. Adulthood presentation is associated with minor symptoms like fatigue and decreased stamina, but dilated cardiomyopathy and arrhythmias and sudden cardiac death have also been reported. Several women have been diagnosed with CDSP after newborn screening identified low carnitine levels in their infants. An asymptomatic adult male with CDSP has also been reported. Other atypical manifestations reported in individuals with CDSP include anemia, proximal muscle weakness and global developmental delays, respiratory distress, arrhythmias, and electrocardiographic abnormalities including long QT syndrome.

Natural History (Important subgroups & survival / recovery)

Newborn screening can identify infants with CDSP and mothers with CDSP. CDSP has typically been associated with infantile metabolic (hepatic) presentation in about half of affected individuals and childhood myopathic (cardiac) presentation in the other half. However, adults with CDSP who have mild, or no symptoms have been reported. The infantile metabolic presentation affects children between age three months and two years with episodes of metabolic decompensation triggered by fasting or common illnesses, particularly vomiting, diarrhea or respiratory tract infections. If children with CDSP are not treated with intravenous dextrose infusion during episodes of metabolic decompensation, they may develop coma and die. The average age of the childhood myopathic presentation is between age two and four years. Death from cardiac failure can occur before the diagnosis is established, indicating that this presentation can be fatal if not treated. Older children with the infantile presentation may also develop myopathic manifestations. One systematic review reported that about 8% of individuals do not experience their first symptom until adulthood. It is unclear whether asymptomatic adults with CDSP have potential health risks due to limited literature and lack of follow up. Pregnant individuals can have decreased stamina or worsening of cardiac arrhythmia during pregnancy. Long-term prognosis is favorable as long as individuals with CDSP remain on carnitine supplementation.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

>1-2 in 100

Sequencing of the SLC22A5 gene can detect at least one pathogenic variant in approximately 70% of individuals with CDSP.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

CDSP has typically been associated with infantile metabolic presentation in about half of affected individuals and childhood myopathic presentation in the other half. Several adults with CDSP who have mild or no symptoms have been reported. Such milder phenotypes are expected to be under ascertained and underdiagnosed; therefore, it is difficult to determine the relative prevalence of different phenotypes associated with CDSP.

Tier 3

>= 40 %

A systematic review of clinical characteristics in 621 individuals with confirmed CDSP (595 by the detection of bi-allelic variants in the SLC22A5 gene) documented symptoms in patients grouped by mode of diagnosis. Penetrance varied based on mode of diagnosis.

• 100% in individuals diagnosed after symptomatic presentation (n=161)

oCardiac symptoms in 72.7% (including 16 individuals that experienced cardiac events)

oNeurological symptoms in 23.6%

oMuscle symptoms in 34.2%

oHepatic symptoms in 30.4%

oMetabolic symptoms in 30.4%

oOnly unspecific symptoms in 2.5%

oDeceased 13.1%

• 69.7% in individuals diagnosed through risk screening (n=109)

• 16.7% in mothers diagnosed after NBS of the child (n=102)

• 10% in individuals diagnosed on NBS (n=249)

Tier 1

Expressivity

The clinical manifestations of systemic primary carnitine deficiency (CDSP) can vary widely with respect to age of onset, organ involvement, and severity of symptoms. The CDSP phenotype encompasses a broad clinical spectrum including metabolic decompensation in infancy, cardiomyopathy in childhood, fatigability in adulthood, or absence of symptoms. Diet provides approximately 75% of daily carnitine requirement. This may play a role in modulating the variability and severity of features in individuals with CDSP, especially in those who remain asymptomatic throughout their lifetime.

Tier 4

A systematic review reported clinical characteristics in 102 mothers diagnosed with CDSP after NBS identified low carnitine in their infants. Of the symptomatic mothers (17/102), 9 experienced exclusively pregnancy-related/nonspecific symptoms, 3 had cardiac symptoms, 4 had muscle symptoms, 1 had hepatic symptoms, and 2 had metabolic symptoms.

Tier 1

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening, https://www.acmg.net/PDFLibrary/Carnitine-Uptake-Defect-ACT-Sheet.pdf.

To establish the extent of disease and needs of an individual diagnosed with CDSP, the following evaluations are recommended:

• Echocardiogram and electrocardiogram

• Bloodwork, including serum creatine kinase (CK), liver transaminases, and pre-prandial blood glucose

• Consultation with a clinical geneticist and/or genetic counselor

Tier 4

The main treatment for CDSP is lifelong oral levocarnitine (L-carnitine) supplementation. Treatment should be initiated as soon as possible. Individuals with CDSP respond well if oral L-carnitine supplementation is started before irreversible organ damage occurs. Metabolic decompensation and skeletal and cardiac muscle function improve with L-carnitine supplementations. Maintaining appropriate plasma carnitine concentrations through oral L-carnitine supplementation and preventing hypoglycemia (with frequent feeding and avoid fasting) typically eliminate the risk of metabolic, hepatic, cardiac, and muscular complications. Hospitalization to administer intravenous glucose is recommended for individuals with CDSP who are required to fast because of medical or surgical procedures or who cannot tolerate oral intake because of an illness such as gastroenteritis.

Tier 4

A systematic review of therapies for metabolic myopathies (including CDSP and others), reported that L-carnitine supplementation was an effective management strategy in treating individuals with genetically confirmed CDSP, based on two small case series (n=2 and 11) and 6 case reports (N=19 individuals with CDSP). When reported, age of diagnosis was birth to 3.5 years and length of follow-up was 8 weeks to 14 years. Three individuals were reported to have resolution of biochemical abnormalities (ammonia, CK, and/or liver enzymes), 10 individuals were reported to have improvement or resolution of cardiac features, 3 individuals had increases in weight, and 3 individuals were described as asymptomatic at follow-up.

Tier 1

Another systematic review of clinical characteristics in 621 individuals with confirmed CDSP (median age at diagnosis 1 year, ranging from birth to 79 years) documented symptoms in patients grouped by mode of diagnosis. Symptoms were rarely (5.6%) observed in children identified by NBS (n=249). The most obvious explanation for this observation would be early initiation of treatment in NBS-identified patients, thus preventing symptoms. Another explanation could be detection of milder phenotypes in the patients identified by screening programs. Three patients identified through NBS died and were reported to have discontinued carnitine supplementation.

Tier 1

Metabolic decompensation and hypoglycemic episodes are treated with glucose in addition to carnitine supplementation. Emergency treatment aims to restore carnitine concentrations and reduce mobilization of fat by providing ample glucose. Early signs of metabolic decompensation may be subtle. Hypoglycemia only occurs at a relatively late stage. The aim of emergency treatment should always be to intervene while blood glucose is normal. A patient’s clinical status may warrant intravenous carnitine and glucose if they cannot be administered orally.

Tier 2

The limited literature regarding asymptomatic adults with CDSP and potential health risks make it unclear if treatment in this population is indicated or warranted. However, because some fatty acid oxidation defects can remain asymptomatic until they result in sudden death or another acute presentation during stress, it has been suggested that asymptomatic individuals with CDSP be treated with L-carnitine supplementation to prevent the possibility of decompensation during intercurrent illness or stress. Repeated attacks of hypoglycemia or sudden death from arrhythmia have been described in individuals with CDSP who discontinue carnitine supplementation.

Tier 3

All individuals with CDSP who are planning to become or are pregnant should meet with a metabolic or genetic specialist ideally before conception to discuss management of carnitine levels during pregnancy. All pregnant individuals with CDSP, including those who are asymptomatic, require close monitoring of plasma carnitine levels and increased carnitine supplementation as needed to maintain normal plasma carnitine levels.

Tier 4

Individuals with cardiomyopathy require management and follow up by specialists in cardiology.

Tier 3

Surveillance

To date, there have been no formal surveillance guidelines for individuals with CDSP. Available recommendations are primarily based on expert opinion. The following evaluations have been suggested:

• Echocardiogram and electrocardiogram. Perform annually during childhood and less frequently in adulthood.

• Plasma carnitine concentration. Monitor frequently until levels reach the normal range, thereafter, measure three times a year during infancy and early childhood, twice a year in older children, and annually in adults.

• Serum CK concentration and liver transaminases. Consider measuring during acute illnesses.

Tier 3

Circumstances to Avoid

Individuals with CDSP should avoid fasting longer than age-appropriate periods.

Tier 4

Nature of Intervention

Nature of Intervention

The intervention is daily, high dose oral L-carnitine supplementation, required for lifelong treatment of the condition. L-carnitine supplementation has relatively few side effects. High doses of oral L-carnitine can cause increased gastrointestinal motility, diarrhea, and intestinal discomfort. Oral L-carnitine can be metabolized by intestinal bacteria to produce trimethylamine, which has a fishy odor. Although carnitine crosses the placenta, animal studies and the limited studies on humans have not demonstrated any teratogenic effects on the developing fetus when the mother was supplemented with carnitine at standard doses.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Several women have been diagnosed with CDSP after newborn screening identified low carnitine levels in their infants.

Context: Adult Pediatric

Tier 1

This disorder is sometimes mistaken for Reye syndrome in children.

Context: Adult Pediatric

Tier 5

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			SLC22A5			212140	0008919

References List

Ayman W El-Hattab. Systemic Primary Carnitine Deficiency. GeneReviews (2016) URL: https://www.ncbi.nlm.nih.gov/books/NBK84551/

CARNITINE DEFICIENCY, SYSTEMIC PRIMARY; CDSP. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 212140, (2020) World Wide Web URL: http://omim.org/

Carnitine transporter deficiency - acute decompensation. BIMDG (2008) URL: https://www.bimdg.org.uk/store/guidelines/ER-CTD-v4_376453_09092016.pdf

Crefcoeur LL, Visser G, Ferdinandusse S, Wijburg FA, Langeveld M, Sjouke B. (2022) Clinical characteristics of primary carnitine deficiency: A structured review using a case-by-case approach. Journal of inherited metabolic disease. 45(1573-2665):386-405.

Magoulas PL, El-Hattab AW. (2012) Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet journal of rare diseases. 7(1750-1172):68.

Manta A, Spendiff S, Lochmüller H, Thompson R. (2021) Targeted Therapies for Metabolic Myopathies Related to Glycogen Storage and Lipid Metabolism: a Systematic Review and Steps Towards a 'Treatabolome'. Journal of neuromuscular diseases. 8(2214-3602):401-417.

Newborn Screening ACT Sheet: Carnitine Uptake Defect; Primary Carnitine Deficiency.. ACMG (2022) URL: https://www.acmg.net/PDFLibrary/Carnitine-Uptake-Defect-ACT-Sheet.pdf

Primary carnitine deficiency. Medline Plus (2014) URL: https://medlineplus.gov/genetics/condition/primary-carnitine-deficiency/

Systemic primary carnitine deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=158