Clinical Diagnosis

The major clinical finding in individuals with Amish lethal microcephaly (MCPHA) is severe microcephaly present at birth [Kelley et al 2002]. Occipitofrontal circumference (OFC) is typically six to 12 standard deviations below the mean.

Recently a child with severe microcephaly, partial absence of the corpus callosum, and closed spinal dysraphism was reported [Siu et al 2010], expanding the phenotype.

Testing

Urinary organic acid 2-ketoglutarate. All affected children of Lancaster Amish heritage reported have highly elevated, at least tenfold-increased levels of the urinary organic acid 2-ketoglutarate, usually in the absence of increased levels of other citric acid cycle intermediates or lactate [Kelley et al 2002].

The patient reported by Siu et al [2010] did not have elevated urinary 2-ketoglutarate but did have elevated plasma concentrations of lactate.

Note: No other metabolic abnormalities are consistently found. However, during intercurrent illnesses such as viral syndromes, some children have metabolic acidosis with increased concentration of lactate in blood and urine.

Molecular Genetic Testing

Gene. SLC25A19 (also known as DNC or MUP1) is the only gene in which mutations are known to cause MCPHA.

Clinical testing

• Sequence analysis. All affected individuals within the Old Order Amish population are homozygous for the same single-base pair substitution, a c.530G>C transversion in SLC25A19 [Rosenberg et al 2002]. The same mutation was identified in an Amish-Mennonite family not closely related to the Lancaster Amish [Siu et al 2010].

• Deletion/duplication analysis is available clinically. However, the usefulness of such testing has not been demonstrated, as no deletions or duplications involving SLC25A19 as causative of Amish lethal microcephaly have been reported.

Table 1. Summary of Molecular Genetic Testing Used in Amish Lethal Microcephaly

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
SLC25A19	Sequence analysis	c.530G>C and other sequence variants 2	100% 3	Clinical
	Deletion/ duplication analysis 4	Deletion/duplication of one or more exons or the whole gene 5	Unknown; none reported to date

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Note that the 100% mutation detection rate is for testing among the Amish; the yield would be expected to be lower in non-Amish individuals.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. No deletions or duplications involving SLC25A13 as causative of Amish lethal microcephaly have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in the Molecular Genetics section (see Table A and/or Molecular Genetics, Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing to identify disease-causing mutations using sequence analysis

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Spiegel et al [2009] reported four sibs, the offspring of consanguineous Arab-Muslim parents, with a homozygous c.373G>A mutation which predicts p.Gly125Ser. They all had the similar and distinctive presentation of acute encephalopathy, striatal necrosis, lactic acidosis, and slowly progressive peripheral neuropathy. This phenotype appears to be distinct from Amish microcephaly: the affected individuals were normocephalic and had childhood onset of metabolic decompensation with permanent neurologic sequelae.

The sibs did not have elevated urinary 2-ketoglutarate but did have elevated plasma concentrations of lactate. No pathology was available.

Natural History

Amish lethal microcephaly (MCPHA) is a distinct disorder with little variability in its presentation, at least among the Old Order Amish from Lancaster County, Pennsylvania [Kelley et al 2002]. Affected infants have severe microcephaly at birth. The cranial vault is extremely underdeveloped as a result of the small brain size. Anterior and posterior fontanels are closed, and ridging from premature sutural fusion may be evident. The facial features are distorted as a result of the profound microcephaly. The only non-CNS physical anomaly is moderate micrognathia. Mild hepatomegaly has been observed in several affected individuals, usually during acute illnesses associated with metabolic acidosis.

Many affected infants have difficulty maintaining body temperature. After the first two or three months of life, increasing irritability of unknown causes commonly develops [Kelley et al 2002]. Although no changes in physical or neurologic examination accompany the irritability, the Lancaster Amish children are more likely to die within 24-48 hours of developing their next viral illness. The average life span of an affected infant is between five and six months among the Lancaster Amish, but the affected Amish-Mennonite child reported by Siu et al [2010] was alive (albeit with severe developmental delay) at age seven years.

Neuropathology. A partial autopsy of an affected four-month-old infant gave insight into the neuropathology of the disorder [Strauss et al 2002]. The severity of the malformation is more pronounced in the anterior portion of the brain. Frontal lobes are smooth and rudimentary. Increasing convolution and lamination progress occipitotemporally. Regions that are most hypoplastic are most disorganized histologically.

No pathology on the case reported by Siu et al [2010] was available.

Genotype-Phenotype Correlations

With only two known mutations, such correlations are difficult to make.

Prevalence

MCPHA has been found primarily in the Old Order Amish who have ancestors in Lancaster County, Pennsylvania. At least 61 affected infants have been born to 33 nuclear families in the past 40 years. In this population, incidence is approximately one in 500 births.

The report of Siu et al [2010] shows that the phenotype is not limited to the Old Order Amish population, although prevalence is difficult to estimate.

Evaluation Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Amish lethal microcephaly (MCPHA), appropriate imaging studies should be performed. Refer to general references on microcephaly for guidance; no recommendations are specific to MCPHA.

Treatment of Manifestations

This disorder is fatal within the first year of life in children of the Old Order Amish of Lancaster County, Pennsylvania. No intervention — including mitochondrial vitamin treatment — has shown promise for treatment or amelioration in this population. However, most experience with this disorder is based on the Old Order Amish; therefore, most clinical experience is based on a single allele. It is now known that this same allele can manifest in a more mild form [Siu et al 2010]. In this case, it was shown that a ketogenic diet improved the acidosis.

Seizures have occurred in some affected infants; the few children who were treated responded well to phenobarbital.

Physical therapy may be considered if the affected child develops contractures or other secondary neurologic manifestations.

Early intervention to stimulate and comfort the infant may be considered.

Support and respite for the family may be needed during the stressful terminal irritability phase of the disease, which can last for several weeks.

Prevention of Primary Manifestations

Routine childhood illnesses should be managed to minimize the acidosis associated with acute illnesses. Many affected infants in the Lancaster Amish population have died during metabolic exacerbations associated with an intercurrent infectious illness.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Vitamin supplementation does not appear to be effective in most patients.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Amish lethal microcephaly (MCPHA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The biologic parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic and have normal urinary excretion of 2-ketoglutarate.

Sibs of a proband

• At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. MCPHA is lethal before reproductive age.

Other family members of a proband. The risk to each sib of the proband's parents of being a carrier is at least 50% and may be 67% (2/3) if the proband's parent had an affected sib.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Fetal ultrasound examination. Three fetal ultrasound examinations performed after 20 weeks' gestation in two pregnancies of babies ultimately found to have MCPHA revealed marked deceleration of head growth [Kelley et al 2002]. The sensitivity and specificity of fetal ultrasound for the prenatal diagnosis of Amish lethal microcephaly has not been evaluated.

Biochemical genetic testing. Prenatal diagnosis by measurement of 2-ketoglutarate in amniotic fluid has also has not been evaluated.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Battaglia A, Carey JC. Microcephaly. In: Rudolph CD, Rudolph AM, eds. Rudolph's Pediatrics. 21 ed. New York: McGraw-Hill; 2003:784-6.
2. Dolce V, Fiermonte G, Runswick MJ, Palmieri F, Walker JE. The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. Proc Natl Acad Sci U S A. 2001;98:2284–8. [PMC free article: PMC30130] [PubMed: 11226231]
3. Dunckelmann RJ, Ebinger F, Schulze A, Wanders RJ, Rating D, Mayatepek E. 2-ketoglutarate dehydrogenase deficiency with intermittent 2-ketoglutaric aciduria. Neuropediatrics. 2000;31:35–8. [PubMed: 10774994]
4. Iacobazzi V, Ventura M, Fiermonte G, Prezioso G, Rocchi M, Palmieri F. Genomic organization and mapping of the gene (SLC25A19) encoding the human mitochondrial deoxynucleotide carrier (DNC). Cytogenet Cell Genet. 2001;93:40–2. [PubMed: 11474176]
5. Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet. 2002;112:318–26. [PubMed: 12376931]
6. Lindhurst MJ, Fiermonte G, Song S, Struys E, De Leonardis F, Schwartzberg PL, Chen A, Castegna A, Verhoeven N, Mathews CK, Palmieri F, Biesecker LG. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Natl Acad Sci U S A. 2006;103:15927–32. [PMC free article: PMC1595310] [PubMed: 17035501]
7. Rosenberg MJ, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard MS, Koch T, Kalikin LM, Makalowska I, Morton DH, Petty EM, Weber JL, Palmieri F, Kelley RI, Schäffer AA, Biesecker LG. Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet. 2002;32:175–9. [PubMed: 12185364]
8. Siu VM, Ratko S, Prasad AN, Prasad C, Rupar CA. Amish microcephaly: Long-term survival and biochemical characterization. Am J Med Genet A. 2010;152A:1747–51. [PubMed: 20583149]
9. Spiegel R, Shaag A, Edvardson S, Mandel H, Stepensky P, Shalev SA, Horovitz Y, Pines O, Elpeleg O. SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann Neurol. 2009;66:419–24. [PubMed: 19798730]
10. Strauss KA, Pfannl R, Morton DH. The neuropathology of Amish lethal microcephaly. Am J Hum Genet. 2002;71S:260.
11. van Bever Y, Balemans W, Duval EL, Jespers A, Eyskens F, van Hul W, Courtens W. Exclusion of OGDH and BMP4 as candidate genes in two siblings with autosomal recessive DOOR syndrome. Am J Med Genet A. 2007;143:763–7. [PubMed: 17343268]

Author Notes

Dr. Lindhurst is a geneticist and senior biologist trained at the University of Chicago. Dr. Biesecker is a clinical geneticist and human geneticist trained at the University of Michigan. Both are based at the National Human Genome Research Institute at the NIH.

Revision History

• 16 June 2011 (me) Comprehensive update posted live

• 5 May 2009 (me) Comprehensive update posted

• 20 December 2005 (me) Comprehensive update posted to live Web site

• 4 September 2003 (me) Review posted to live Web site

• 24 June 2003 (mjl) Original submission