Amish lethal microcephaly

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Amish lethal microcephaly is a disorder in which infants are born with an unusually small head (microcephaly) and underdeveloped brain. Infants with Amish lethal microcephaly have a sloping forehead and an extremely small head size. They may also have an unusually small lower jaw (micrognathia) and an enlarged liver (hepatomegaly).

Affected infants may have seizures and difficulty maintaining their body temperature. Often, they become very irritable starting in the second or third month of life. A compound called alpha-ketoglutaric acid can be detected in their urine (alpha-ketoglutaric aciduria), and during episodes of viral illness they tend to develop elevated levels of acid in the blood and tissues (metabolic acidosis). Infants with this disorder typically feed adequately but do not develop skills such as purposeful movement or the ability to track faces and sounds. Affected infants live only about six months.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the SLC25A19 gene cause Amish lethal microcephaly.

The SLC25A19 gene provides instructions for producing a protein that is a member of the solute carrier (SLC) family of proteins. Proteins in the SLC family transport various compounds across the membranes surrounding the cell and its component parts. The protein produced from the SLC25A19 gene transports a molecule called thiamine pyrophosphate into the mitochondria, the energy-producing centers of cells. This compound is involved in the activity of a group of mitochondrial enzymes called the dehydrogenase complexes, one of which is the alpha-ketoglutarate dehydrogenase complex. The transport of thiamine pyrophosphate into the mitochondria is believed to be important in brain development.

All known individuals with Amish lethal microcephaly have a mutation in which the protein building block (amino acid) alanine is substituted for the amino acid glycine at position 177 of the SLC25A19 protein, written as Gly177Ala or G177A. Researchers believe that this mutation interferes with the transport of thiamine pyrophosphate into the mitochondria and the activity of the alpha-ketoglutarate dehydrogenase complex, resulting in the abnormal brain development and alpha-ketoglutaric aciduria seen in Amish lethal microcephaly.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Amish lethal microcephaly occurs in approximately 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Cerebellar vermis hypoplasia · Very frequent (99-80%)

Underdevelopment of the vermis of cerebellum.

Death in infancy · Very frequent (99-80%)

Death within the first 24 months of life.

Feeding difficulties · Very frequent (99-80%)

Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.

Irritability · Very frequent (99-80%)

An emotional state characterized by negative feelings of heightened frustration, annoyance, or feeling upset, often triggered by internal factors (e.g., fatigue, hunger, unfulfilled desires) or external factors (e.g., social or environmental challenges). Irritability may be unpredictable, and is accompanied by a lowered threshold for emotional reactivity and observable features (speech, facial expressions, or psychomotor activity).

Metabolic acidosis · Very frequent (99-80%)

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.

Microcephaly · Very frequent (99-80%)

Head circumference below 2 standard deviations below the mean for age and gender.

Micrognathia · Very frequent (99-80%)

Developmental hypoplasia of the mandible.

Optic atrophy · Very frequent (99-80%)

Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.

Organic aciduria · Very frequent (99-80%)

Excretion of non-amino organic acids in urine.

Severe global developmental delay · Very frequent (99-80%)

A severe delay in the achievement of motor or mental milestones in the domains of development of a child.

Sloping forehead · Very frequent (99-80%)

Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.

Agenesis of corpus callosum · Frequent (79-30%)

Absence of the corpus callosum as a result of the failure of the corpus callosum to develop, which can be the result of a failure in any one of the multiple steps of callosal development including cellular proliferation and migration, axonal growth or glial patterning at the midline.

Hypotonia · Frequent (79-30%)

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.

Lissencephaly · Frequent (79-30%)

A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.

Other findings in the same source

From: Orphanet

Additional reported features include Osteoporosis (Frequent (79-30%)); Spina bifida (Frequent (79-30%)); Temperature instability (Frequent (79-30%)); Ventriculomegaly (Frequent (79-30%)); Limb hypertonia (Frequent (79-30%)); Bilateral tonic-clonic seizure (Occasional (29-5%)); Cleft soft palate (Occasional (29-5%)); Decreased fetal movement (Occasional (29-5%)); Decreased skull ossification (Occasional (29-5%)); Hepatomegaly (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Amish lethal microcephaly is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Amish lethal microcephaly. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.