Selenoprotein Deficiency Disorder: The Inherited Condition That Shows What Selenium Proteins Do

Most people who read about low selenium are reading about diet: soil, food and intake. This page is about something else. Selenoprotein deficiency disorder is a rare inherited condition in which the body can have selenium available and still fail to build selenium into proteins, because a piece of the building machinery is faulty. It was first reported in people in 2005. Because it reduces many selenium proteins at once, the families who have it have shown researchers what those proteins appear to do in the thyroid system, muscle, skin, ears, testes, blood vessels and brain.

Everything known about it comes from case reports and small series of families. The sections below give what those reports found, what was tried, and how far such a small record can be taken. For ordinary low selenium from diet, the matching page is Selenium Deficiency; for the mineral itself, Selenium.

Table of Contents

  1. A Shortage of Machinery, Not of Selenium
  2. How Selenocysteine Is Built Into a Protein
  3. The Thyroid Test Pattern That Exposed It
  4. The Genes Reported So Far
  5. The Other Organs Reported
  6. What Was Tried, and What Selenium Did
  7. The Separate Early-Onset Brain Disease
  8. How Rare It Is and the Limits of the Case Series
  9. Key Research Papers
  10. Connections
  11. Featured Videos

A Shortage of Machinery, Not of Selenium

Selenium does most of its work inside proteins. It is carried there as selenocysteine, an amino acid containing selenium, and proteins that contain it are called selenoproteins. Most of them are enzymes that handle oxidation and reduction chemistry (Labunskyy and colleagues, 2014). A 2003 genome analysis counted 25 selenoproteins in the human body (Kryukov and colleagues, 2003), and later reviews still use that figure or "more than 25" (Santesmasses and Gladyshev, 2021; Schoenmakers and Chatterjee, 2021).

In dietary deficiency, the raw material runs short and the machinery is intact, which is why a shortfall in intake generally responds to more selenium. In selenoprotein deficiency disorder the position is reversed. Blood selenium does read low, but that low reading reflects a shortage of the selenium-containing blood proteins, selenoprotein P and glutathione peroxidase 3 (Schoenmakers and Chatterjee, 2021). A team studying affected siblings concluded that selenium "is obviously not a limiting factor" in these people when a regular daily intake is provided (Schomburg and colleagues, 2009).

So two people can have the same low blood selenium result for opposite reasons. That difference is the reason this condition gets its own page, and the section on treatment below shows what follows from it.

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How Selenocysteine Is Built Into a Protein

Selenocysteine is often called the 21st amino acid, and it is unusual in two ways. It is the only genetically encoded amino acid that is assembled while already sitting on its own carrier molecule, its transfer RNA, in humans (Agamy and colleagues, 2010). And it has no code word of its own. The cell reuses a three-letter code, UGA, whose normal meaning is "stop making this protein" (Labunskyy and colleagues, 2014). To read that stop signal as selenocysteine instead, the cell needs a dedicated set of parts.

The 2021 review by Schoenmakers and Chatterjee lays out the sequence:

  1. The carrier. A special transfer RNA, made from the TRU-TCA1-1 gene, is loaded first with the amino acid serine.
  2. The conversion. An enzyme adds a phosphate to the serine. A selenium-containing compound, selenophosphate, is then used by the enzyme encoded by the SEPSECS gene in the final step that produces selenocysteine on the carrier.
  3. The signal. Messenger RNA for each selenoprotein carries a folded signal near its tail end, called a selenocysteine insertion sequence. It marks that this particular stop code means selenocysteine.
  4. The adaptor. Selenocysteine insertion sequence binding protein 2, the product of the SECISBP2 gene, binds that signal and acts as a scaffold, gathering the ribosome, the loaded carrier and a dedicated delivery factor, the selenocysteine-specific elongation factor encoded by the EEFSEC gene.
  5. Insertion. The ribosome places selenocysteine in the growing protein and carries on past the code that would otherwise have stopped it.

A fault in a part used by every selenoprotein can lower many of them together, which is why the condition affects so many tissues. Complete loss appears incompatible with life in mice: those lacking the selenocysteine transfer RNA die in the womb (Dumitrescu and colleagues, 2005). In people, the reports describe partial loss. The original team judged that incomplete loss of SECISBP2 function probably explained the mild picture they saw (Dumitrescu and colleagues, 2005). The 2021 review adds a likely reason: most reported SECISBP2 mutations produce a premature stop early in the gene, upstream of a second start point, which still permits a shorter version of the protein holding its working region.

Not all selenoproteins fall equally. Even with ordinary low selenium, "housekeeping" selenoproteins are better protected than "stress-related" ones, an order of priority whose basis remains unclear (Schoenmakers and Chatterjee, 2021). The genetic faults show this order too, as described under the genes below.

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The Thyroid Test Pattern That Exposed It

The condition came to light through a blood test result that did not fit. In 2005 Dumitrescu and colleagues described three of seven siblings with signs of abnormal thyroid hormone metabolism, and an unrelated child with a similar picture. The children had growth that lagged for a time along with abnormal thyroid tests (Dumitrescu and colleagues, 2010). Skin cells from the family showed reduced activity of a thyroid-activating enzyme, deiodinase type 2. Working back through the genes needed to make that enzyme led the team to SECISBP2, the first selenocysteine insertion defect described in humans.

The link is direct. The thyroid gland mainly releases thyroxine, and the active hormone is triiodothyronine. Three enzymes called deiodinases regulate this conversion inside cells, and all three are selenoproteins (Dumitrescu and colleagues, 2010). When they run short, the hormone pattern shifts in a recognisable way, which later families repeated (Fu and colleagues, 2020; Çatli and colleagues, 2018):

The 2024 European Thyroid Association guideline calls this combination the biochemical hallmark of the condition (Persani and colleagues, 2024). A 2026 report shows it in one teenager: raised free thyroxine, normal thyroid-stimulating hormone, low free triiodothyronine and a serum selenium of 14.37 micrograms per litre, with speech delay and learning difficulties (Özdemir Akgün and colleagues, 2026).

A pattern shared with other causes

High thyroid hormone without a suppressed thyroid-stimulating hormone is not unique to this condition. A 2024 review of the pattern lists laboratory interference (abnormal binding proteins, antibodies, biotin), resistance to thyroid hormone, monocarboxylate transporter 8 deficiency and thyroid-stimulating-hormone-secreting pituitary tumours among its causes. Its authors report that a structured approach ending in genetic testing or specialised imaging can reach the right diagnosis and may spare people unnecessary tests or inappropriate treatment (Moran and colleagues, 2024).

The harm from missing it is on record. In one series, a case went undetected for 20 years because SECISBP2 was not on the neurodevelopmental gene panel used, and the person's confusing thyroid results led to antithyroid treatment instead (Stoupa and colleagues, 2024). For more on the tests themselves, see Reverse Triiodothyronine and Selenium Test.

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The Genes Reported So Far

Three genes in the selenocysteine pathway were the main ones covered in the reviews to 2021 (Schoenmakers and Chatterjee, 2020; 2021), and a fourth has been added since. Authors do not all draw the boundaries in the same place: the 2021 review treats all three as causes of systemic selenoprotein deficiency, while the 2024 guideline uses "selenoprotein deficiency" for the two with the thyroid pattern.

SECISBP2

This is the best-documented form. People affected carry faults on both copies of the gene, either the same fault twice or two different ones. Reviews report no features in people who carry a single faulty copy (Schoenmakers and Chatterjee, 2021). Schoenmakers and colleagues (2010) showed that synthesis of most of the known selenoproteins fell in people with this form, and it is the source of the broad organ picture described in the next section.

TRU-TCA1-1

This gene makes the selenocysteine transfer RNA itself. The first patient, reported in 2016, had abdominal pain, fatigue, muscle weakness and low plasma selenium. The fault sharply reduced stress-related selenoproteins while largely sparing housekeeping ones, a selective pattern that differs from SECISBP2 (Schoenmakers and colleagues, 2016). The same variant, known as C65G, was then found in a second family. A 13-year-old carrying two copies, seen for Hashimoto's disease, had no complaints and no added symptoms over six years without treatment, though his thyroid tests drifted and his total selenium at the last visit was 91 micrograms per litre against a normal range of 95 to 125. His father, with one copy, had normal thyroid tests apart from a moderately raised reverse triiodothyronine, and selenium of 143 micrograms per litre. The authors concluded this variant is "not exclusively causative" of disrupted selenoprotein synthesis (Geslot and colleagues, 2021).

SEPSECS and EEFSEC

These two act in the same pathway but mainly produce brain disease. They are described separately below.

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The Other Organs Reported

The 2010 report that named this a multisystem selenoprotein deficiency disorder moved the condition well beyond the thyroid (Schoenmakers and colleagues, 2010). Later families added further features. Not every patient has every feature, and severity varies widely.

Growth and development

Most reported cases were found in childhood, with failure to thrive, short stature, delayed bone age and delayed development (Schoenmakers and Chatterjee, 2021). Variation is large: a 10-year-old Turkish boy had attention-deficit disorder and muscle weakness but no delay in growth or bone age (Çatli and colleagues, 2018), and the 2024 guideline notes that untreated people can reach normal height (Persani and colleagues, 2024).

Muscle

Fatigue and weakness are attributed at least partly to a progressive muscular dystrophy of the spine and the muscles nearest the trunk. It closely resembles the disease caused by faults in the gene for selenoprotein N, one specific selenoprotein (Schoenmakers and colleagues, 2010; Schoenmakers and Chatterjee, 2021). The guideline lists reduced breathing at night among the issues to monitor. Dietary selenium-related muscle problems are covered on Selenium Deficiency: Muscle Weakness.

Skin

Some patients are unusually sensitive to sunlight. In the 2010 report, skin was short of antioxidant selenium enzymes, cells carried more reactive oxygen species, and skin was more susceptible to ultraviolet oxidative damage, which the authors suggested may underlie the sensitivity (Schoenmakers and colleagues, 2010).

Hearing

Mild, high-frequency nerve-type hearing loss in both ears is seen in some patients. It worsens in older patients, and the 2021 review suggests that oxidative damage in the hearing system may be the cause. Hearing loss can also be there from birth, as in a 3-year-old Korean girl (Yang and colleagues, 2026).

Fertility

In the 2010 report, azoospermia (no sperm in the semen) came with failure of the late stages of sperm production and a lack of selenoproteins that are concentrated in the testis (Schoenmakers and colleagues, 2010). The 2021 review describes this finding in one adult man, so the size of the fertility risk across the condition cannot be stated from this record.

Immune cells, fat and insulin

The 2010 report found low selenoproteins in blood cells alongside impaired multiplication of T lymphocytes, abnormal cytokine release and shorter telomeres. It also found a result that runs against expectation: raised oxidative stress came with better insulin sensitivity, both throughout the body and in cells, matching mice lacking glutathione peroxidase 1. Reviews also describe increased body fat (Schoenmakers and Chatterjee, 2021).

The aorta

The most serious late finding so far arrived in 2023. Schoenmakers and colleagues reported four patients with SECISBP2 mutations who developed early-onset, progressive widening of the ascending aorta caused by a breakdown of the vessel's middle wall layer (cystic medial necrosis). Aortic aneurysms can tear or burst suddenly and be fatal. Zebrafish with the gene disrupted, and male mice with it disrupted throughout the body or in vessel smooth muscle, developed a similar disease. Aortas from patients and animal models showed raised reactive oxygen species, oxidative DNA damage and smooth muscle cell death (Schoenmakers and colleagues, 2023). The 2024 guideline lists surveillance for this widening among its statements. General background is on Aortic Aneurysm.

The nervous system

The picture here has changed. A 2021 review noted that an early-onset central nervous system disease was not a feature of SECISBP2 or TRU-TCA1-1 cases. Then a 2024 series of six families reported four probands with absent speech, autistic features and seizures, and in two of them the gene was found before the thyroid pattern was known (Stoupa and colleagues, 2024). A 2026 overview lists skeletal muscle, the endocrine system, the immune system and particularly the brain as sensitive to selenoprotein loss (Schweizer and Fabiano, 2026).

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What Was Tried, and What Selenium Did

Selenium itself

The obvious idea was tried early. Schomburg and colleagues (2009) gave three affected and two unaffected siblings selenomethionine-rich yeast at 100, 200 or 400 micrograms a day and sodium selenite at 400 micrograms a day, for one month each.

The authors' reading was that a rise in blood selenium here did not indicate better selenoprotein production. The number on the test can improve while the problem stays where it was. Later reviews reported the same: supplements raised total selenium in some patients with no clinical or biochemical effect (Schoenmakers and Chatterjee, 2021). The 2024 European Thyroid Association guideline states that it does not recommend selenium supplementation in SECISBP2 deficiency, classing it as a strong statement resting on low-quality evidence, the case-series level of its scale (Persani and colleagues, 2024). This is a statement about this one genetic condition, and not about ordinary dietary deficiency. The upper limit and the harms of excess are on Selenium Toxicity.

TRU-TCA1-1 is an open question. The 2021 review thought supplementation deserved evaluation in that form. In human cells engineered with the C65G mutation, however, selenoprotein expression was no longer sensitive to added selenium (Vindry and colleagues, 2023). The guideline lists this as undetermined in patients.

Triiodothyronine (liothyronine)

Giving the active hormone directly addresses the step the deiodinases can no longer perform. Reviews report that it can correct the abnormal thyroid hormone picture (Schoenmakers and Chatterjee, 2020), and the guideline reports better linear growth, alone or with growth hormone. Individual reports:

Growth hormone

A Japanese boy without growth hormone deficiency received growth hormone from age 4. Over six years his height moved from 3.4 to 1.7 standard deviations below average, without bone maturation speeding up. Six months of added triiodothyronine, begun at 10, almost normalised thyroid tests and improved both growth and bone maturation (Hamajima and colleagues, 2012). This is one child, with no comparison group.

Vitamin E and other antioxidants

Oxidative damage suggested a different target. In one person with SECISBP2 mutations, lipid oxidation products in blood were higher than in controls. Vitamin E (alpha-tocopherol acetate, 100 milligrams a day) for two years brought them down to control levels, and they rose again after seven months off treatment (Saito and colleagues, 2015). That result concerns a blood marker in one person. It does not show any change in muscle, hearing or aorta. In the aortic research, antioxidant exposure or iron chelation prevented oxidative damage in a patient's cells and prevented the aortic disease in the zebrafish model (Schoenmakers and colleagues, 2023). Reviews describe antioxidant therapy as reducing damage in patients' cells and tissues while stating that long-term benefit remains undefined (Schoenmakers and Chatterjee, 2021).

Everything else

For muscular dystrophy, male infertility, hearing loss and neurodegeneration, a 2020 review reported no specific therapies as yet (Schoenmakers and Chatterjee, 2020). Care is supportive, and the reported measures include breathing support at night and hearing aids. The guideline lists monitoring of growth and development in childhood, periodic magnetic resonance imaging of muscle, breathing and sleep studies, and surveillance of hearing and the thoracic aorta. A 2025 narrative review proposes low-to-moderate exercise and an antioxidant-rich diet, based on reasoning, while stating that no targeted or controlled studies of lifestyle changes exist in these groups (Rodolfi and colleagues, 2025).

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The Separate Early-Onset Brain Disease

Faults in the same pathway can produce a very different illness. It is treated here as a distinct condition, and it is not what the thyroid-led reports above describe.

SEPSECS

The SEPSECS enzyme (O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase) performs the last step in making selenocysteine. In 2010 Agamy and colleagues showed that SEPSECS mutations cause a recessive progressive cerebellocerebral atrophy (a shrinking of the back and main parts of the brain) in Jewish families of Iraqi and Moroccan ancestry, who carried founder mutations. It was later reported under the name pontocerebellar hypoplasia type 2D. Children in three families with SEPSECS faults showed newborn irritability, stiff or twisting paralysis of all four limbs, almost no development, nerve damage and raised lactate, and brain tissue showed severe damage, with loss of myelin and neurons (Anttonen and colleagues, 2015).

Severity spans a wide range. Iwama and colleagues (2016) described two families with slower progression and milder atrophy, and a 23-year-old woman with slowly progressive ataxia and cognitive impairment has also been reported (van Dijk and colleagues, 2018). A 2026 international cohort of 27 people, with 13 new variants, sorted the disease into three courses: severe early onset with cerebellar or cerebral atrophy, milder early onset with gradual decline, and mild late onset. The pons was involved in fewer than half, so the authors proposed renaming it SEPSECS-related neurodevelopmental disorder (Killam and colleagues, 2026).

Thyroid results help separate the two conditions. In that cohort, thyroid measurements suggested a defect in converting thyroxine to triiodothyronine in only 1 of 8 people tested (Killam and colleagues, 2026). Why one pathway fault produces mainly brain disease and another mainly a thyroid-and-muscle picture is not settled in the records reviewed here.

EEFSEC

The delivery factor has now been implicated too. In 2025 Laugwitz and colleagues described nine people from eight families with faults on both copies of EEFSEC. They had global developmental delay, progressive spasticity, ataxia and seizures, with cerebellar underdevelopment and atrophy on imaging. Selenoprotein levels were lower in their skin cells. A 2026 zebrafish study reported underdeveloped midbrain and hindbrain in fish lacking the gene, and proposed that the disease begins as a developmental problem and not purely as later degeneration (Xia and colleagues, 2026). That finding is from a fish model. General background on the symptom is on Cerebellar Ataxia.

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How Rare It Is and the Limits of the Case Series

No population rate for this condition appeared in any record read for this page. Its rarity is expressed by counting families. A 2020 report stated that eight families with recessive SECISBP2 mutations had been reported before its own two (Fu and colleagues, 2020). The 2021 review counted 11 families from diverse backgrounds, and the 2024 series added six more families (Stoupa and colleagues, 2024). Two unrelated people with the same TRU-TCA1-1 mutation are described in the guideline. For SEPSECS, the count went from 11 patients in 2016 (Iwama and colleagues, 2016), to 20 in the 2021 review, to the 27-person cohort of 2026. For scale, a 2025 review gives about 1 in 20,000 newborns for resistance to thyroid hormone beta, and describes it as the most common among this group of inherited thyroid signalling disorders (Rodolfi and colleagues, 2025). Santesmasses and Gladyshev (2021) looked at the allele frequencies of the disease variants in the general population, but that work does not give a count of affected people.

Several limits follow from numbers this small:

Within those limits, the record has a clear shape. People with this condition show what happens when selenium proteins cannot be made well, whatever the diet. The selenium study also shows that a higher selenium reading and a better-working selenium protein are different things.

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Key Research Papers

  1. Dumitrescu AM, Liao XH, Abdullah MS, Lado-Abeal J, Majed FA, Moeller LC, Boran G, Schomburg L, Weiss RE, Refetoff S. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet. 2005;37(11):1247-52. PubMed PMID: 16228000
  2. Dumitrescu AM, Di Cosmo C, Liao XH, Weiss RE, Refetoff S. The syndrome of inherited partial SBP2 deficiency in humans. Antioxid Redox Signal. 2010;12(7):905-20. PubMed PMID: 19769464
  3. Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbaschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O'Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna KK, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, Chatterjee K. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest. 2010;120(12):4220-35. PubMed PMID: 21084748
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PubMed Topic Searches

  1. PubMed: SECISBP2 mutations
  2. PubMed: selenoprotein deficiency disorder
  3. PubMed: TRU-TCA1-1 selenocysteine transfer RNA
  4. PubMed: SEPSECS
  5. PubMed: EEFSEC deficiency

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