H63D Syndrome

H63D syndrome is a very rare clinical phenotype based on a homozygous HFE H63D gene mutation of the HFE gene. This mutation is associated with diverse diseases, but H63D syndrome is the only known specific expression of a homozygous HFE-H63D mutation to date.[1]

Epidemiology

The homozygous HFE-H63D mutation is the cause of classic and treatable hemochromatosis in only 6.7% of its carriers.[2]

H63D syndrome is independently a distinct entity, and the incidence in homozygous carriers of the H63D mutation is approximately 10%.[3]

Pathomechanism

Ideally, laboratory symptoms include excessive transferrin saturation based on a relative deficiency of transferrin. The transferrin value is pre and postprandial stable. Thus, the body does not respond to nutritive iron supplementation by providing more transferrin. This allows toxic “non-transferrin bound iron (NTBI)” to enter various parenchymal tissues and trigger degenerative changes there by oxidation cascades. Iron overload primarily affects nerve cells in the substantia nigra and in the basal ganglia. Here, a slowly progressive degeneration occurs.[4][5][6][7] In addition, many H63D syndrome patients experience nonspecific activation of the innate immune systems, which can additionally lead to spontaneously occurring, passive autoimmune reactions of variable type and severity.[8]

Variants

There are patients with a homozygous H36D mutation whose symptoms are not exclusively caused by NTBI-type iron but by other oxidative inflammatory cascades. They show an almost identical clinical picture. To better delineate them, the “International H63D Syndrome Research Consortium” has proposed the name "H63D syndrome type 2."[9]

Symptoms

H63D syndrome shares quite some symptoms with Wilson’s disease with the most common being:[10] [11][12]

Neurologic symptoms
  • Variable motor dysfunction, possibly including Parkinson's symptoms late in the course.
  • Postural instability analogous to Parkinson's disease.
  • Narcolepsy, often with cataplexy - when manifestation of degenerative and irreversible brain damage has already occurred.
  • Thinking disorders: Often highly severe and usually primarily obsessive in nature, compatible with dysfunction of the basal ganglia. They are often misrecognized - especially in the early phase of the disease - in the sense of a misdiagnosis as "mental suffering". If thought disorders are in the foreground, a timely diagnosis is therefore often delayed.
  • Tic disorders: variable Tourette's-like tics occurring with a strongly fluctuating course.
  • Hyperkinesias, sometimes with risk of self-injury
  • disturbance of REM sleeps, with risk of self-injury
  • Dementia of varying severity from mild cognitive impairment to full-blown dementia, most compatible with Lewy body dementia. Clinically relevant changes occur in 30% to 60% of H63D patients, depending on the study. Variability is due to nonstandardized measurement procedures and cut-off values, especially in mild cognitive impairment.
  • Cognitive impairments: This aspect is often masked by performance reserves over time (months to years), especially in previously cognitively strong patients, but can lead to significant failures in daily life and work under high sensory and complex content input.
  • Decline in intelligence quotients despite preserved selective performance in areas that can be relatively well delineated diagnostically.
  • Impairment of executive functions with preserved long-term memory.

The occurrence or worsening of narcolepsy with a decrease in tic symptomatology is indicative of progression of brain damage.

Symptoms in other organ systems
  • Cardiac damage and dysfunction, especially conduction defects and arrhythmias, occasionally progressing to heart failure
  • Liver damage (even early in the course, often an unexplained steatosis).
  • Excessive episodes of the inert part of the immune system with highly variable autoimmune reactions, including periods of decreased defense of the adaptive immune system.
  • Fibrosis in various organ systems, including skin
  • Impaired motility in the digestive system, usually constipation, less commonly bloating
  • testicular atrophy in male patients, sometimes with degenerative signs on sonography
  • Skin symptoms of variable nature (including impetigo, pruritus, hyperresponsiveness, hidradenitis suppurativa, etc.).
  • Rarely: kidney involvement, eye diseases due to NTBI-induced oxidative processes, hearing loss, etc.
  • Rather later in the course, with already structurally altered substantia nigra: urge incontinence in all manifestations.
  • Chronic eosinophilia with possible structural damage to the heart.[13]
  • Disorders of adrenal and other endocrine organ function due to oxidative-induced inflammation processes with functional or structural organ damage caused by infiltration processes in the adrenal cortex region. (primary adrenal insufficiency).[14][15] Subsequently, there is clinically relevant dysfunction of the HPA axis as well as adrenaline synthesis (sympathetic adrenal medullary axis) with erratic adrenaline excesses.[16]
  • Damage to the islet cells of the pancreas with development of type-3 diabetes mellitus (Europeean definition or another form of dysregulated insulin secretion.[17]
  • Onset of mitochondriopathy (disruption of cellular respiratory chains) if genetic predisposition to the disease is present.

Because of the variety of symptoms, the syndrome is usually recognized relatively late, especially if laboratory diagnostics do not detect all relevant parameters of iron metabolisms or mitochondriopathy.

Diagnostics

Laboratory

The typical constellation of findings is indicative: The patients show a postprandial non-responsive and too low transferrin level (hypotransferrinemia) with high transferrin saturation (usually > 50%) and low ferritin value. Multiple tests are obligatory due to physiologically induced fluctuations. Mild persistent eosinophilia and basophilia are sometimes found in parallel. In case of outbreak of a dormant mitochondriopathy due to NTBI-induced oxidative stress postprandial lactate may be significantly elevated (often more than 3 mmol/l).

Imaging

On transcranial sonography, the substantia nigra presents as in Parkinson's disease hyperechogenic, but the symptoms need not be identical. With rare exceptions, MRI remains unremarkable.

The scintigraphy (DAT scan) may also be abnormal. Due to radiation exposure and advances in the field of sonography, DAT scans are now mostly used only in the context of clinical trials for this condition.

Pathohistology

There is deposition of free iron in the brain and other tissues. NTBI iron cannot be stained in histology (e.g., with the Berlin Blue Reaction). This is a common source of error or reason for false-negatives.

Molecular biology

Homozygous H63D mutation of the HFE gene is detectable by molecular biology using a genetic test. Detection of a heterozygousmutation excludes H63D syndrome.

Differential diagnoses

If homozygous H63D mutation cannot be detected in the laboratory with evidence of iron deposition in the brain and abnormal levels of iron metabolisms, other genetic disorders of iron utilization should be considered primarily. Differential diagnoses include:

Therapy

No causal treatment for H63D syndrome is currently (2023) available. Free iron not bound to proteins cannot be removed from the organism by phlebotomy and related procedures. Instead, the patient would merely suffer a further drop in his already usually low ferritin level. Consequently, dialysis and iron chelators are also ineffective and are more likely to provoke lethal side effects than to improve the clinical picture.[18] They further lower the ferritin, which is usually too low anyway, without binding the NTBI present in the cells in significant amounts.

Dietary control of iron intake thus remains the best prevention against severe symptoms in cases diagnosed in time. If organ damage already exists, a low iron diet may slow progression somewhat. However, such a diet should only be followed under the supervision of a physician in patients with H63D syndrome, because an overload of NTBI in the body may coexist with a deficiency of vital ferritin.

Various drugs can be used to alleviate some symptoms - some in off-label use. In addition, medical assistive devices such as orthotics, protective headgears, walkers, or wheelchairs are useful.[19]

Social medical aspects

Often, patients' language abilities remain normative for a prolonged period of time, making dementia-related decline initially unnoticeable to the social environment.

H63D patients with milder forms of cognitive decline or with isolated executive dysfunction are often overwhelmed in everyday life. The reason for this is that the long-term memory of the patients is rarely impaired, which the social environment misinterprets as a sign of intact brain function. Intensive socio-medical counseling of caregivers is therefore an important cornerstone in the management of H63D syndrome.

Literature

Sources
  1. Shirazi, Ali; Honda, Riku; Rocha, Fabio; et al. (2023) H63D Syndrome Type-1: What you should know about it. Zenodo openAIRE publishing, June 2023. https://doi.org/10.5281/zenodo.7998160
  2. Kelley et al Iron overload is rare in patients homozygous for the H63D mutation Can J Gastroenterol Hepatol 2014
  3. Incidence of a clinically relevant H63D syndrome in carriers of a homozygous mutation of HFE gene H63D, accessed 09/05/2022
  4. Papadopoulos et al. Prevalence of Narcolepsy in Patients with H63D Syndrome. Sys Rev Pharm 2021; 12(9): 508-510
  5. Nasrullah H, Nasrullah A, Ijaz N, et al. (November 23, 2022) H63D Homozygous Mutation: An Unusual Cause of Deranged Liver Function Test in an Elderly Patient . Cureus 14(11): e31840. DOI 10.7759/cureus.31840
  6. Castiella A, Zapata E, de Juan MD, Otazua P, Fernandez J, Zubiaurre L, Arriola JA; Gipuzkoa Hemochromatosis Group. Significance of H63D homozygosity in a Basque population with hemochromatosis. J Gastroenterol Hepatol. 2010 Jul;25(7):1295-8. doi: 10.1111/j.1440-1746.2010.06247.x. PMID 20594259.
  7. Castiella A, Urreta I, Zapata E, de Juan MD, Emparanza JI; Burnia Group. H63/H63D genotype and the H63D allele are associated in patients with hyperferritinemia to the development of metabolic syndrome. Eur J Intern Med. 2020 Feb;72:106-107. doi: 10.1016/j.ejim.2019.11.021. Epub 2019 Nov 30. PMID 31796245
  8. Shirazi, A., Honda, R., Rocha, F., (2023). H63D Syndrome Type-1: What you should know about it (2023). Zenodo openAIRE publishing, June 2023. https://doi.org/10.5281/zenodo.7998160
  9. Ivanova et al, H63D Mutation Syndrome Type-2, Zenodo openAIRE publishing, 2023
  10. Ivanova, Olga; Wilson, Jonathan; Tudor, Adrian; et al. (2022). H63D syndrome (Oslo Syndrome) is clinically the iron sibling of Wilson's disease. Swabian Research Insitute. Zenodo openAIRE publishing: https://doi.org/10.5281/zenodo.7978271
  11. Ali-Rahmani F, Grigson PS, Lee S, Neely E, Connor JR, Schengrund CL. H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment. Neurobiol Aging. 2014 Jun;35(6):1511.e1-12. doi: 10.1016/j.neurobiolaging.2013.12.014. Epub 2013 Dec 25. PMID 24439478
  12. Berg, T. (2020). Hemochromatosis & Related Syndromes: Including the Most Important Information about the H63D Syndrome. Printed and distributed by BoD on behalf of Lothian Publishing, Edinburgh
  13. Séguéla et al, Eosinophilic cardiac disease: Molecular, clinical and imaging aspects, Arch Cardiovasc Dis, 2015
  14. Banaszkiewicz et al, Endocrine disorders in patients with hereditary hemochromatosis, European Journal of Translational and Clinical Medicine, 2018
  15. Charmandari et al, Adrenal insufficiency, The Lancet, 2014
  16. Lazar et al, Endocrinology: Patients suffering from H63D syndrome are at high risk to develop clinically relevant endocrine abnormalities affecting their adrenal glands as well as their HPA and SAM axes, Zenodo openAIRE publishing, 2022
  17. Ivanova et al, Diabetes in patients with iron metabolism disorders - including H63D homozygous mutation syndrome, Zenodo openAIRE publishing, 2023
  18. pdf Wirkstoff aktuell - Eine Information der KBV im Rahmen des § 73 (8) SBG V in Zusammenarbeit mit der Arzneimittelkommission der Deutschen Ärzteschaft: Deferasirox (Exjade), Ausgabe 5-2008
  19. Seideman et al Preprint: Injury protection strategies for H63D syndrome patients suffering from cataplexy 2021
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