Rare Disorders—Challenging and Underdiagnosed

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (10 October 2023) | Viewed by 15670

Special Issue Editor


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Guest Editor
Department of Pediatric Neurology, Faculty of Medical Sciences, Medical University of Silesia, Katowice, Poland
Interests: epilepsy; rare diseases; nerometabolic disorders; neurodevelopmental disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rare disorders known as orphan diseases affect a small percentage of the population. There is no consensus or definition for these diseases. In the European Union, a disease is considered to be rare if it affects fewer than 1:2000. At present, about 7000 rare disorders have been detected. Most metabolic disorders or inborn errors of metabolism have neurological presentations, and rare disorders affecting the pediatric brain are complex conditions. The underlying mechanisms leading to structural damage are diverse, and the diagnostic imaging manifestations are often nonspecific. Early and specific diagnoses may prove crucial for further management and treatment.

In recent years, extraordinary progress has been made in developing effective treatments for rare disorders. However, there are still many challenges, especially regarding extended gene panels for investigating complex phenotypes. Along with the development and availability of genetic analyzes, by using next-generation sequencing over the last decade, an increasing knowledge of the genes and gene families that can be involved in pathogenesis helps to gain insights into the pathomechanisms underlying different forms of rare disorders.

Papers that contain an analysis of metabolic perturbations (effect of drugs, nutrients and the environment on metabolism/metabolic pathways) or metabolic pathways, networks, and inborn errors of metabolism are especially welcome.

On behalf of the Editorial Office, we invite you to contribute your research papers, review articles, and interesting case reports for peer-review and possible publication.

Dr. Justyna Paprocka
Guest Editor

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Keywords

  • rare disorders
  • neurometabolic disorders
  • neurological symptoms
  • treatment
  • diagnostics

Published Papers (7 papers)

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13 pages, 262 KiB  
Review
Disorders of Copper Metabolism in Children—A Problem too Rarely Recognized
by Sabina Więcek and Justyna Paprocka
Metabolites 2024, 14(1), 38; https://doi.org/10.3390/metabo14010038 - 7 Jan 2024
Cited by 1 | Viewed by 1368
Abstract
Copper plays an important role in metabolic processes. Both deficiency and excess of this element have a negative effect and lead to pathological conditions. Copper is a cofactor of many enzymatic reactions. Its concentration depends on the delivery in the diet, the absorption [...] Read more.
Copper plays an important role in metabolic processes. Both deficiency and excess of this element have a negative effect and lead to pathological conditions. Copper is a cofactor of many enzymatic reactions. Its concentration depends on the delivery in the diet, the absorption in enterocytes, transport with the participation of ATP7A/ATP7B protein, and proper excretion. Copper homeostasis disorders lead to serious medical conditions such as Menkes disease (MD) and Wilson’s disease (WD). A mutation in the ATP7A gene is the cause of Menkes disease, it prevents the supply of copper ions to enzymes dependent on them, such as dopamine β-hydroxylase and lysyl oxidase. This leads to progressive changes in the central nervous system and disorders of the connective tissue. In turn, Wilson’s disease is an inherited autosomal recessive disease. It is caused by a mutation of the ATP7B gene encoding the ATP7B protein which means excess copper cannot be removed from the body, leading to the pathological accumulation of this element in the liver and brain. The clinical picture is dominated by the liver, neurological, and/or psychiatric symptoms. Early inclusion of zinc preparations and chelating drugs significantly improves the prognosis in this group of patients. The aim of the study is to analyse, based on the latest literature, the following factors: the etiopathogenesis, clinical picture, diagnostic tests, treatment, prognosis, and complications of disease entities associated with copper disturbances: Menkes disease and Wilson’s disease. In addition, it is necessary for general practitioners, neurologists, and gastroenterologists to pay attention to these disease entities because they are recognized too late and too rarely, especially in the paediatric population. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
19 pages, 684 KiB  
Review
Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation
by Evelina Maines, Michele Moretti, Nicola Vitturi, Giorgia Gugelmo, Ilaria Fasan, Livia Lenzini, Giovanni Piccoli, Vincenza Gragnaniello, Arianna Maiorana, Massimo Soffiati, Alberto Burlina and Roberto Franceschi
Metabolites 2023, 13(4), 563; https://doi.org/10.3390/metabo13040563 - 16 Apr 2023
Viewed by 2210
Abstract
The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver [...] Read more.
The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms “propionic acidemia” OR “propionate” AND “cardiomyopathy” OR “Long QT syndrome”. We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation–contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin–angiotensin–aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
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18 pages, 353 KiB  
Review
Ataxia in Neurometabolic Disorders
by Konrad Kaminiów, Izabella Ryguła and Justyna Paprocka
Metabolites 2023, 13(1), 47; https://doi.org/10.3390/metabo13010047 - 28 Dec 2022
Cited by 3 | Viewed by 2562
Abstract
Ataxia is a movement disorder that manifests during the execution of purposeful movements. It results from damage to the structures of the cerebellum and its connections or the posterior cords of the spinal cord. It should be noted that, in addition to occurring [...] Read more.
Ataxia is a movement disorder that manifests during the execution of purposeful movements. It results from damage to the structures of the cerebellum and its connections or the posterior cords of the spinal cord. It should be noted that, in addition to occurring as part of many diseases, pediatric ataxia is a common symptom in neurometabolic diseases. To date, there are more than 150 inherited metabolic disorders that can manifest as ataxia in children. Neuroimaging studies (magnetic resonance imaging of the head and spinal cord) are essential in the diagnosis of ataxia, and genetic studies are performed when metabolic diseases are suspected. It is important to remember that most of these disorders are progressive if left untreated. Therefore, it is crucial to include neurometabolic disorders in the differential diagnosis of ataxia, so that an early diagnosis can be made. Initiating prompt treatment influences positive neurodevelopmental outcomes. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
16 pages, 630 KiB  
Review
COQ8A-Ataxia as a Manifestation of Primary Coenzyme Q Deficiency
by Justyna Paprocka, Magdalena Nowak, Piotr Chuchra and Robert Śmigiel
Metabolites 2022, 12(10), 955; https://doi.org/10.3390/metabo12100955 - 8 Oct 2022
Cited by 7 | Viewed by 3063
Abstract
COQ8A-ataxia is a mitochondrial disease in which a defect in coenzyme Q10 synthesis leads to dysfunction of the respiratory chain. The disease is usually present as childhood-onset progressive ataxia with developmental regression and cerebellar atrophy. However, due to variable phenotype, it may [...] Read more.
COQ8A-ataxia is a mitochondrial disease in which a defect in coenzyme Q10 synthesis leads to dysfunction of the respiratory chain. The disease is usually present as childhood-onset progressive ataxia with developmental regression and cerebellar atrophy. However, due to variable phenotype, it may be hard to distinguish from other mitochondrial diseases and a wide spectrum of childhood-onset cerebellar ataxia. COQ8A-ataxia is a potentially treatable condition with the supplementation of coenzyme Q10 as a main therapy; however, even 50% may not respond to the treatment. In this study we review the clinical manifestation and management of COQ8A-ataxia, focusing on current knowledge of coenzyme Q10 supplementation and approach to further therapies. Moreover, the case of a 22-month-old girl with cerebellar ataxia and developmental regression will be presented. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
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20 pages, 371 KiB  
Review
Stroke-like Episodes in Inherited Neurometabolic Disorders
by Natalia Będkowska, Aneta Zontek and Justyna Paprocka
Metabolites 2022, 12(10), 929; https://doi.org/10.3390/metabo12100929 - 30 Sep 2022
Cited by 2 | Viewed by 2242
Abstract
Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in neuroimaging procedures are described as stroke-like lesions (SLLs). It is crucial to distinguish SLEs from cerebral infarction or intracerebral hemorrhage, mainly due to the [...] Read more.
Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in neuroimaging procedures are described as stroke-like lesions (SLLs). It is crucial to distinguish SLEs from cerebral infarction or intracerebral hemorrhage, mainly due to the variety in management. Another significant issue to underline is the meaning of the main pathogenetic hypotheses in the development of SLEs. The diagnostic process is based on the patient’s medical history, physical and neurological examination, neuroimaging techniques and laboratory and genetic testing. Implementation of treatment is generally symptomatic and includes L-arginine supplementation and adequate antiepileptic management. The main aim of the current review was to summarize the basic and actual knowledge about the occurrence of SLEs in various inherited neurometabolic disorders, discuss the possible pathomechanism of their development, underline the role of neuroimaging in the detection of SLLs and identification of the electroencephalographic patterns as well as histological abnormalities in inherited disorders of metabolism. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)

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9 pages, 1446 KiB  
Case Report
A Successful Bisphosphonates Monotherapy in Spinal Form of Paediatric Chronic Recurrent Multifocal Osteomyelitis (CRMO)—Case Report
by Aleksandra Opala, Jagoda Hofman, Michał Hutny, Aleksandra Wylazlowska and Paweł Matusik
Metabolites 2023, 13(3), 344; https://doi.org/10.3390/metabo13030344 - 25 Feb 2023
Cited by 1 | Viewed by 1479
Abstract
Chronic recurrent multifocal osteomyelitis (CRMO) is a non-infectious inflammatory disorder resulting from the multifocal bone and bone marrow lesions with periodic relapses and remissions and with an uncertain prognosis. Treatment options in CRMO are based on expert opinion and relatively small groups of [...] Read more.
Chronic recurrent multifocal osteomyelitis (CRMO) is a non-infectious inflammatory disorder resulting from the multifocal bone and bone marrow lesions with periodic relapses and remissions and with an uncertain prognosis. Treatment options in CRMO are based on expert opinion and relatively small groups of patients. A nine-year-old female patient with no significant past medical history presented with compression fractures and multifocal bone lesions in the thoracic and lumbar spine, as shown in imaging (CT, MRI). Densitometry revealed a diffuse decrease in bone density. Based on the patient’s clinical image and above examinations, the other possible aetiologies—infectious (including tuberculosis), neoplasms, Langerhans cell histiocytosis—were ruled out, which led to eventual final diagnosis—CRMO. The patient was successfully treated with pamidronate infusion initiated in cycles over three consecutive days every 3 months. In addition to clinical improvement, there was a significant remission of inflammation and bone structure healing assessed by MRI after four treatment cycles. Intravenous bisphosphonates usage seems to be a good therapeutic option in CRMO paediatric patients with spinal localization of the lesions complicated by compressive fractures. However, more data, based on larger patient populations, are needed to provide a detailed paediatric CRMO treatment algorithm. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
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16 pages, 2793 KiB  
Case Report
Mucopolysaccharidosis Type 1 among Children—Neuroradiological Perspective Based on Single Centre Experience and Literature Review
by Magdalena Machnikowska-Sokołowska, Aleksandra Myszczuk, Emilia Wieszała, Dominika Wieja-Błach, Ewa Jamroz and Justyna Paprocka
Metabolites 2023, 13(2), 209; https://doi.org/10.3390/metabo13020209 - 31 Jan 2023
Cited by 1 | Viewed by 1701
Abstract
Mucopolysaccharidosis 1 (MPS 1) is a group of rare lysosomal genetic disorders resulting from the accumulation of undegraded glycosaminoglycans (GAGs) leading to multiorgan damage. Neurological symptoms vary from mild to severe. Neuroimaging—mainly magnetic resonance (MRI)—plays a crucial role in disease diagnosis and monitoring. [...] Read more.
Mucopolysaccharidosis 1 (MPS 1) is a group of rare lysosomal genetic disorders resulting from the accumulation of undegraded glycosaminoglycans (GAGs) leading to multiorgan damage. Neurological symptoms vary from mild to severe. Neuroimaging—mainly magnetic resonance (MRI)—plays a crucial role in disease diagnosis and monitoring. Early diagnosis is of the utmost importance due to the necessity of an early therapy implementation. New imaging tools like MR spectroscopy (MRS), semiquantitative MRI analysis and applying scoring systems help substantially in MPS 1 surveillance. The presented analysis of neuroimaging manifestations is based on 5 children with MPS 1 and a literature review. The vigilance of the radiologist based on knowledge of neuroradiological patterns is highlighted. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
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