NAD(P)HX epimerase deficiency

What it is

From: Orphanet

A rare neurometabolic disease characterized by infantile onset of rapidly progressive neurological deterioration, typically precipitated by a febrile illness. Patients present with hypotonia, loss of previously acquired motor milestones and cognitive skills, ataxia, nystagmus, tremor, seizures, tetraparesis, and respiratory failure, eventually resulting in a vegetative state. Imaging of the brain and spinal cord may show white matter abnormalities, cerebral atrophy, cerebellar edema, and spinal myelopathy. Subacute development of extensive bullous skin lesions within weeks of onset of neurological symptoms has also been reported.

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.

Ataxia · Very frequent (99-80%)

Ataxia refers to impaired coordination of voluntary muscle movement. Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).

Confusion · Frequent (79-30%)

Lack of clarity and coherence of thought, perception, understanding, or action.

Developmental regression · Frequent (79-30%)

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

Dysarthria · Frequent (79-30%)

Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.

Dysphagia · Frequent (79-30%)

Difficulty in swallowing.

EEG with abnormally slow frequencies · Frequent (79-30%)

EEG with abnormally slow frequencies.

Gait disturbance · Frequent (79-30%)

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

Hyperintensity of cerebral white matter on MRI · Frequent (79-30%)

A brighter than expected signal on magnetic resonance imaging emanating from the cerebral white matter.

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.

Increased CSF lactate · Frequent (79-30%)

Increased concentration of lactate in the cerebrospinal fluid.

Respiratory failure · Frequent (79-30%)

A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.

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.

Tremor · Frequent (79-30%)

An unintentional, oscillating to-and-fro muscle movement about a joint axis.

Anxiety · Occasional (29-5%)

Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.

Other findings in the same source

From: Orphanet

Additional reported features include Atypical behavior (Occasional (29-5%)); Brain atrophy (Occasional (29-5%)); Cerebellar atrophy (Occasional (29-5%)); Cerebral edema (Occasional (29-5%)); Leukoencephalopathy (Occasional (29-5%)); Localized skin lesion (Occasional (29-5%)); Myelopathy (Occasional (29-5%)); Myoclonus (Occasional (29-5%)); Nystagmus (Occasional (29-5%)); Ptosis (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: Orphanet

Infancy

Inheritance in the source

From: Orphanet

Autosomal recessive

Frequency and the population described

From: Orphanet

Reported case(s): 11.0; 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 epimerase 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 epimerase 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.