# Presentation: 184923

## Medium chain acyl-CoA dehydrogenase(MCAD) deficiency

- Sophia S. Wang, Ph.D.
- Office of Genetics and Disease Prevention
- Centers for Disease Control and Prevention

## Newborn Screening for MCAD deficiency

**MA**

**OH**

**WI**

**CA**

**NC**

**PA**

**VT**

**SD**

**RI**

**ME**

**IN**

**IL**

**Notes:**
Currently, Colorado and Montana universally screen all newborns in their states for CF.  Wisconsin implemented NBS for CF in 1994 after ten years of follow up from their clinical trial.  On February 1 of this year, Massachusetts initiated a pilot NBS program for CF where parents have the option of informed dissent.  California is currently determining the optimal screening protocol for their state since their ethnically diverse population is much different from that of Colorado, Montana or Wisconsin.  CA is planning to begin screening all newborns for CF in the year 2000.

## MCAD

- One of five acyl-CoA dehydrogenases
- Tetrameric flavoprotein essential for the beta-oxidation of medium chain fatty acids
- Oxidative reductase enzyme that catalyzes the 1st step of the medium-chain fatty acid oxidation

## MCAD - genetics

- Located on chromosome one: 1p31
- Autosomal recessive disorder
- 26 MCAD mutations (9 in OMIM)
- No genotypic/phenotypic correlation

## G985A (K304E)

- Point mutation G985A or K304E (glutamate substituted for lysine at position 304)
- 90% of alleles
- 81% homozygous
- 18% compound heterozygous
- Frequency of G985A homozygosity: 1/6,500-20,000
- Frequency of G985A heterozygosity: 1/40-100

## MCAD deficiency

- Inherited error of fatty acid metabolism
- Abnormal protein product and subsequent inefficient enzymatic activity to metabolize medium chain fatty acids

## MCAD deficiency - epidemiology

- Prevalence
- United Kingdom: 1/10,000 – 1/25,000
- Incidence
- United Kingdom: 1/22,222 *(Pollitt & Leonard, 1998)*
- Pennsylvania: 1/13,192 *(Ziadeh et al, 1995)*

## Clinical presentation

- Hypoglycemia
- Vomiting
- Lethargy
- Encephalopathy
- Respiratory arrest
- Hepatomegaly

-      Seizures
-      Apnea
-      Cardiac arrest
-      Coma
-      Sudden &    	unexpected death

## Long-term outcomes

- Developmental and behavioral disabilities
- Chronic muscle weakness
- Failure to thrive
- Cerebral palsy
- Attention deficit disorder

## Risk factors/disease severity

- Fasting
- Infection
- Immunization
- Age of 1st episode
- Family history

## Treatment

- For acute attacks:
- Large intravenous doses of glucose
- Long-term management:
- Avoidance of fasting (preventing stress caused by fasting)
- Maintaining high-carbohydrate, reduced fat diet
- Carnitine supplementation

## Diagnosis

- Tandem mass spectrometry (MS/MS)
- Measures octanoylcarnitine on filter paper blood spot
- Urine organic acid profile (HPLC)
- Confirmation
- DNA-based tests (PCR for specific mutations)
- Confirmation

## Criteria for Universal Screening

- Natural history understood
- Incidence in relevant populations known
- Associated with significant morbidity/mortality
- Effective treatment available
- Period before onset during which intervention effective

*HTA, 1997*

## Rationale for MCAD NBS

- 	Natural history understood
- Incidence in relevant populations known
- Associated with significant morbidity/mortality
- Effective treatment available
- Period before onset during which intervention effective

*HTA, 1997*

## What can we learn from current programs?

- Program assurance/evaluation
- Short-term & long-term process & outcome measures
- Test measures
- Clinical validity & clinical utility
- Population-based data on disorder
- Incidence, prevalence, gene penetrance

## Core Functions of Public Health

**Policy**

**Assurance**

**Evaluation**

- Identification of problem

- Mobilization of necessary efforts & resources

- Assurance that programs are in place and services are received

*Institute of Medicine, 1988*

## Core Functions in Newborn Screening

**Assessment**

**Policy**

**Assurance**

**Evaluation**

- Assessing whether newborn testing for specific disorder is beneficial - epidemiological data, research, surveillance, clinical trials,    meta-analysis

- Based on data collected in assessment, modify program (i.e., add or delete disorder from screening program)

- Ensuring that screening program is in place, that all newborns are screened, that proper treatment and services  are received; F/U

***DATA drive policy***

*Institute of Medicine, 1988*

## Assurance/Evaluation

- Methods for evaluating short-term and long-term process & outcome measures.

- 		_Short-term              __	__Long-term_
- 		proportion of           	proportion of
- Process 	newborns                 	children receiving
-                  	adequately tested     	adequate treatment
- 		proportion of	      		proportion of Outcome    	newborns                	children with
- 		with premature     		adverse outcome
-                   	mortality		       	(e.g., mental
-                   	(e.g., sudden &   		retardation)
- 		unexpected death)

## Test measures

- Clinical validity
- the accuracy of a genetic test in predicting the phenotype (e.g., disease outcome).
- Clinical utility
- measures of the benefits and risks of early detection in persons whom disease is detected
- determines whether adverse outcomes can in fact be altered/prevented.

*Holtzman, 1997*

## Clinical validity of testing for MCAD

- Dependent on definition of phenotype
- Natural history of disorder needs to be understood (e.g., clinical outcomes).
- Understand penetrance of mutations (e.g., will a test predict who will manifest symptoms?)

## Clinical utility of testing for MCAD

- How effective is testing in preventing adverse outcomes (e.g., sudden & unexpected death, morbidity measures)?
- Depends on outcome data and long-term follow up of affected children

## Population screening programs

- Population-based data on disorder
- Elucidate natural history
- Incidence
- Prevalence
- Clinical outcomes
- Determine penetrance of mutations

## Summary

- Need to ensure follow-up beyond diagnosis
- Define and collect appropriate data for:
- Program assurance/evaluation
- Short- & long-term process & outcome measures
- Test measures
- Clinical validity & clinical utility
- Population-based data on disorder
- Incidence, prevalence, gene penetrance