NAD(P)HX dehydratase deficiency

What it is

From: Orphanet

A rare neurometabolic disease characterized by infantile onset of repeated episodes of developmental regression and neurodegeneration, often triggered by febrile illnesses. Patients present with lethargy, hypotonia, irritability, gait ataxia, loss of speech, movement disorder, seizures, ophthalmoplegia, and hearing loss. Brain imaging shows generalized cerebral atrophy and bilateral basal ganglia abnormalities. Extensive skin lesions, cardiomyopathy, and pancytopenia have been reported in association. The condition is fatal in the first years of life.

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.

Developmental regression · Very frequent (99-80%)

Loss of developmental skills, as manifested by loss of developmental milestones.

Abnormal blistering of the skin · Frequent (79-30%)

The presence of one or more bullae on the skin, defined as fluid-filled blisters more than 5 mm in diameter with thin walls.

Anemia · Frequent (79-30%)

A reduction in erythrocytes volume or hemoglobin concentration.

Cerebral atrophy · Frequent (79-30%)

Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.

Decreased activity of mitochondrial respiratory chain · Frequent (79-30%)

Decreased activity of the mitochondrial respiratory chain.

EEG abnormality · Frequent (79-30%)

Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.

Elevated circulating C-reactive protein concentration · Frequent (79-30%)

The concentration of C-reactive protein in the blood circulation is above the upper limit of normal.

Elevated circulating creatine kinase concentration · Frequent (79-30%)

The activity of creatine kinase in the blood circulation is above the upper limit of normal.

Gait disturbance · Frequent (79-30%)

The term gait disturbance can refer to any disruption of the ability to walk.

Increased CSF lactate · Frequent (79-30%)

Increased concentration of lactate in the cerebrospinal fluid.

Increased circulating lactate concentration · Frequent (79-30%)

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).

Localized skin lesion · Frequent (79-30%)

A lesion of the skin that is located in a specific region rather than being generalized.

Myopathy · Frequent (79-30%)

A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.

Seizure · Frequent (79-30%)

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.

Other findings in the same source

From: Orphanet

Additional reported features include Vomiting (Frequent (79-30%)); Abnormal basal ganglia morphology (Occasional (29-5%)); Ataxia (Occasional (29-5%)); Cardiomyopathy (Occasional (29-5%)); Cataract (Occasional (29-5%)); Cerebellar edema (Occasional (29-5%)); Conductive hearing impairment (Occasional (29-5%)); Congestive heart failure (Occasional (29-5%)); Dystonia (Occasional (29-5%)); Elevated circulating aspartate aminotransferase concentration (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: Orphanet

Childhood; Infancy

Inheritance in the source

From: Orphanet

Autosomal recessive

Frequency and the population described

From: Orphanet

Reported case(s): 6.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

Understanding the inheritance label

From: MedlinePlus Genetics

An autosomal recessive pattern usually involves disease-causing changes in both copies of a gene. Parents may each carry one altered copy without having the condition themselves. A genetic counsellor can explain carrier testing and reproductive implications using the actual laboratory findings, rather than the condition name alone.

Which doctor should you see?

The suggested department for discussing NAD(P)HX dehydratase deficiency is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / 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.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for NAD(P)HX dehydratase deficiency. 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.