Raras
Buscar doenças, sintomas, genes...
Doença do metabolismo das aminas biogênicas
ORPHA:79169DOENÇA RARA

O triptofano é um aminoácido utilizado na biossíntese de proteínas, sendo codificado pelo codão UGG. Ele contém, como todo aminoácido, um grupo amino (básico) e um grupo carboxilo (ácido); sua cadeia lateral consiste num indol, o que faz dele um aminoácido aromático e apolar. No pH fisiológico, o triptofano é um zwitterion: o grupo amino (pKa = 9.39) encontra-se protonado (–NH3+) e o grupo carboxila (pKa = 2.38) encontra-se deprotonado ( –COO−). Absorve luz ultravioleta.

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Introdução

O que você precisa saber de cara

📋

Doença rara do metabolismo e transporte de neurotransmissores, caracterizada por rigidez, anormalidades motoras e oculares, choro inapropriado, estridor e comprometimento cognitivo. Pode apresentar microcefalia e anormalidades vasculares.

Medicamentos
9 registrados
ELADOCAGENE EXUPARVOVEC, EDROPHONIUM, PHENYLEPHRINE

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9 medicamentos registrados
Ver detalhes, fases e interações →
ELADOCAGENE EXUPARVOVECEDROPHONIUMPHENYLEPHRINECLONIDINENITROPRUSSIDEPROPRANOLOLISOPROTERENOLATROPINEMETOCLOPRAMIDE
🏥
SUS: Cobertura mínimaScore: 20%
Centros em: PA, PR, SC, RS, ES +8
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Do básico ao detalhe, leia no seu ritmo

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Sinais e sintomas

O que aparece no corpo e com que frequência cada sintoma acontece

Partes do corpo afetadas

🧠
Neurológico
25 sintomas
💪
Músculos
8 sintomas
📏
Crescimento
7 sintomas
😀
Face
6 sintomas
🫃
Digestivo
5 sintomas
🫘
Rins
5 sintomas

+ 77 sintomas em outras categorias

Características mais comuns

Rigidez
Anormalidade do movimento ocular
Choro inapropriado
Anormalidade da coordenação
Estridor
Discinesia orofacial
149sintomas
Sem dados (149)

Os sintomas variam de pessoa para pessoa. Abaixo estão as 149 características clínicas mais associadas, ordenadas por frequência.

RigidezRigidity
Anormalidade do movimento ocularAbnormality of eye movement
Choro inapropriadoInappropriate crying
Anormalidade da coordenaçãoAbnormality of coordination
EstridorStridor

Linha do tempo da pesquisa

Publicações por ano — veja quando o interesse científico cresceu
Anos de pesquisa1
Últimos 10 anos200publicações
Pico2026171 papers
Linha do tempo
2025Hoje · 2026
Publicações por ano (últimos 10 anos)

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Genética e causas

O que está alterado no DNA e como passa nas famílias

Genes associados

6 genes identificados com associação a esta condição.

THTyrosine 3-monooxygenaseDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to L-Dopa (PubMed:15287903, PubMed:1680128, PubMed:17391063, PubMed:24753243, PubMed:34922205, PubMed:8528210, Ref.18). In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity (By similarity).

LOCALIZAÇÃO

Cytoplasm, perinuclear regionNucleusCell projection, axonCytoplasmCytoplasmic vesicle, secretory vesicle, synaptic vesicle

VIAS BIOLÓGICAS (1)
Catecholamine biosynthesis
MECANISMO DE DOENÇA

Segawa syndrome autosomal recessive

A form of DOPA-responsive dystonia presenting in infancy or early childhood. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Some cases present with parkinsonian symptoms in infancy. Unlike all other forms of dystonia, it is an eminently treatable condition, due to a favorable response to L-DOPA.

EXPRESSÃO TECIDUAL(Tecido-específico)
Substância negra
45.8 TPM
Hipotálamo
14.1 TPM
Brain Caudate basal ganglia
5.4 TPM
Glândula adrenal
4.2 TPM
Brain Nucleus accumbens basal ganglia
3.6 TPM
OUTRAS DOENÇAS (1)
TH-deficient dopa-responsive dystonia
HGNC:11782UniProt:P07101
TSPOAP1Peripheral-type benzodiazepine receptor-associated protein 1Candidate gene tested inRestrito
FUNÇÃO

Required for synaptic transmission regulation (PubMed:33539324). It probably controls the recruitment of voltage-gated calcium channels to the presynaptic membrane, and modulates neurotransmitter release

LOCALIZAÇÃO

CytoplasmMitochondrion

VIAS BIOLÓGICAS (6)
Serotonin Neurotransmitter Release CycleGlutamate Neurotransmitter Release CycleNorepinephrine Neurotransmitter Release CycleAcetylcholine Neurotransmitter Release CycleDopamine Neurotransmitter Release Cycle
MECANISMO DE DOENÇA

Dystonia 22, adult-onset

A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT22AO is an autosomal recessive form characterized by focal dystonia or tremor and mild cognitive impairment.

EXPRESSÃO TECIDUAL(Ubíquo)
Córtex cerebral
88.0 TPM
Brain Anterior cingulate cortex BA24
77.8 TPM
Cerebelo
74.0 TPM
Brain Frontal Cortex BA9
72.3 TPM
Cérebro - Amígdala
59.8 TPM
OUTRAS DOENÇAS (3)
dystonia 22, juvenile-onsetdystonia 22, adult-onsetTH-deficient dopa-responsive dystonia
HGNC:16831UniProt:O95153
DBHDopamine beta-hydroxylaseDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Catalyzes the hydroxylation of dopamine to noradrenaline (also known as norepinephrine), and is thus vital for regulation of these neurotransmitters

LOCALIZAÇÃO

Cytoplasmic vesicle, secretory vesicle lumenCytoplasmic vesicle, secretory vesicle, chromaffin granule lumenSecretedCytoplasmic vesicle, secretory vesicle membraneCytoplasmic vesicle, secretory vesicle, chromaffin granule membrane

VIAS BIOLÓGICAS (1)
Catecholamine biosynthesis
MECANISMO DE DOENÇA

Orthostatic hypotension 1

A form of orthostatic hypotension due to congenital dopamine beta-hydroxylase deficiency. Orthostatic hypotension, also known as postural hypotension, is a finding defined as a 20-mm Hg decrease in systolic pressure or a 10-mm Hg decrease in diastolic pressure occurring 3 minutes after a person has risen from supine to standing. Symptoms include dizziness, blurred vision, and sometimes syncope. ORTHYP1 is an autosomal recessive condition apparent from infancy or early childhood and characterized by low plasma and urinary levels of norepinephrine and epinephrine, and episodic hypoglycemia.

EXPRESSÃO TECIDUAL(Tecido-específico)
Fígado
23.6 TPM
Glândula adrenal
2.9 TPM
Pituitária
2.6 TPM
Córtex cerebral
2.5 TPM
Nervo tibial
2.2 TPM
OUTRAS DOENÇAS (1)
orthostatic hypotension 1
HGNC:2689UniProt:P09172
MAOAAmine oxidase [flavin-containing] ADisease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

Catalyzes the oxidative deamination of primary and some secondary amine such as neurotransmitters, with concomitant reduction of oxygen to hydrogen peroxide and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:18391214, PubMed:20493079, PubMed:24169519, PubMed:8316221). Preferentially oxidizes serotonin (PubMed:20493079, PubMed:24169519). Also catalyzes the oxidative deamination of kynuramine to 3-(2-amino

LOCALIZAÇÃO

Mitochondrion outer membrane

VIAS BIOLÓGICAS (7)
Norepinephrine Neurotransmitter Release CycleMetabolism of serotoninBiogenic amines are oxidatively deaminated to aldehydes by MAOA and MAOBEnzymatic degradation of dopamine by COMTEnzymatic degradation of Dopamine by monoamine oxidase
MECANISMO DE DOENÇA

Brunner syndrome

A form of X-linked non-dysmorphic mild intellectual disability. Male patients are affected by borderline intellectual deficit and exhibit abnormal behavior, including disturbed regulation of impulsive aggression. Obligate female carriers have normal intelligence and behavior.

EXPRESSÃO TECIDUAL(Ubíquo)
Tecido adiposo
133.9 TPM
Intestino delgado
131.6 TPM
Esôfago - Muscular
125.8 TPM
Bladder
118.4 TPM
Artéria tibial
116.5 TPM
OUTRAS DOENÇAS (1)
Brunner syndrome
HGNC:6833UniProt:P21397
DDCAromatic-L-amino-acid decarboxylaseDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin

LOCALIZAÇÃO

VIAS BIOLÓGICAS (2)
Serotonin and melatonin biosynthesisCatecholamine biosynthesis
MECANISMO DE DOENÇA

Aromatic L-amino-acid decarboxylase deficiency

An inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. It causes developmental and psychomotor delay, poor feeding, lethargy, ptosis, intermittent hypothermia, gastrointestinal disturbances. The onset is early in infancy and inheritance is autosomal recessive.

EXPRESSÃO TECIDUAL(Tecido-específico)
Rim - Córtex
38.2 TPM
Intestino delgado
36.5 TPM
Cólon transverso
19.2 TPM
Rim - Medula
13.9 TPM
Fígado
13.5 TPM
OUTRAS DOENÇAS (1)
aromatic L-amino acid decarboxylase deficiency
HGNC:2719UniProt:P20711
SLC18A2Synaptic vesicular amine transporterDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports a variety of catecholamines such as dopamine, adrenaline and noradrenaline, histamine, and indolamines such as serotonin (PubMed:23363473, PubMed:

LOCALIZAÇÃO

Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membraneCytoplasmic vesicle, secretory vesicle membraneCell projection, axonCell projection, dendrite

VIAS BIOLÓGICAS (3)
Serotonin Neurotransmitter Release CycleDopamine Neurotransmitter Release CycleNorepinephrine Neurotransmitter Release Cycle
MECANISMO DE DOENÇA

Parkinsonism-dystonia 2, infantile-onset

An autosomal recessive disorder characterized by infantile onset of abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. Some patients have variable degrees of developmental delay.

EXPRESSÃO TECIDUAL(Tecido-específico)
Vagina
8.0 TPM
Ovário
6.9 TPM
Cervix Endocervix
6.0 TPM
Cervix Ectocervix
5.9 TPM
Pulmão
5.4 TPM
OUTRAS DOENÇAS (1)
brain dopamine-serotonin vesicular transport disease
HGNC:10935UniProt:Q05940

Medicamentos e terapias

ELADOCAGENE EXUPARVOVECPhase 2

Mecanismo: DDC exogenous gene

EDROPHONIUMPhase 1

Mecanismo: Acetylcholinesterase inhibitor

PHENYLEPHRINEPhase 1

Mecanismo: Adrenergic receptor alpha-1 agonist

CLONIDINEPhase 1

Mecanismo: Adrenergic receptor alpha-2 agonist

NITROPRUSSIDEPhase 1

Mecanismo: Soluble guanylate cyclase activator

PROPRANOLOLPhase 1

Mecanismo: Beta-1 adrenergic receptor antagonist

ISOPROTERENOLPhase 1

Mecanismo: Adrenergic receptor beta agonist

ATROPINEPhase 1

Mecanismo: Muscarinic acetylcholine receptor M1 antagonist

METOCLOPRAMIDEPhase 1

Mecanismo: Serotonin 3a (5-HT3a) receptor antagonist

Ver mais no OpenTargets

Variantes genéticas (ClinVar)

1,278 variantes patogênicas registradas no ClinVar.

🧬 TH: NM_000360.4(TH):c.645-15T>G ()
🧬 TH: NM_000360.4(TH):c.696-19T>C ()
🧬 TH: NM_000360.4(TH):c.197A>C (p.Asp66Ala) ()
🧬 TH: NM_000360.4(TH):c.1002G>A (p.Gly334=) ()
🧬 TH: NM_000360.4(TH):c.91-834C>T ()
Ver todas no ClinVar

Diagnóstico

Os sinais que médicos procuram e os exames que confirmam

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Tratamento e manejo

Remédios, cuidados de apoio e o que precisa acompanhar

Pipeline de tratamentos
Pipeline regulatório — de medicamentos já aprovados a drogas em pesquisa exploratória.
2Fase 21
1Fase 18
Medicamentos catalogadosEnsaios clínicos· 9 medicamentos · 0 ensaios
Carregando informações de tratamento...

Onde tratar no SUS

Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)

🇧🇷 Atendimento SUS — Doença do metabolismo das aminas biogênicas

Centros de Referência SUS

21 centros habilitados pelo SUS para Doença do metabolismo das aminas biogênicas

Centros para Doença do metabolismo das aminas biogênicas

Detalhes dos centros

Hospital Universitário Prof. Edgard Santos (HUPES)

R. Dr. Augusto Viana, s/n - Canela, Salvador - BA, 40110-060 · CNES 0003808

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital de Apoio de Brasília (HAB)

AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Estadual Infantil e Maternidade Alzir Bernardino Alves (HIABA)

Av. Min. Salgado Filho, 918 - Soteco, Vila Velha - ES, 29106-010 · CNES 6631207

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital das Clínicas da UFG

Rua 235 QD. 68 Lote Área, Nº 285, s/nº - Setor Leste Universitário, Goiânia - GO, 74605-050 · CNES 2338424

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital das Clínicas da UFMG

Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

NUPAD / Faculdade de Medicina UFMG

Av. Prof. Alfredo Balena, 189 - 5 andar - Centro, Belo Horizonte - MG, 30130-100 · CNES 2183226

Serviço de Referência

Rota
Erros Inatos do Metabolismo

Hospital Universitário João de Barros Barreto

R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas da Universidade Federal de Pernambuco

Av. Prof. Moraes Rego, 1235 - Cidade Universitária, Recife - PE, 50670-901 · CNES 2561492

Atenção Especializada

Rota
Erros Inatos do Metabolismo

Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)

R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas da UFPR

R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Pedro Ernesto (HUPE-UERJ)

Blvd. 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro - RJ, 20551-030 · CNES 2280221

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira (IFF/Fiocruz)

Av. Rui Barbosa, 716 - Flamengo, Rio de Janeiro - RJ, 22250-020 · CNES 2269988

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Onofre Lopes (HUOL)

Av. Nilo Peçanha, 620 - Petrópolis, Natal - RN, 59012-300 · CNES 2408570

Atenção Especializada

Rota
Erros Inatos do Metabolismo

Hospital São Lucas da PUCRS

Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre - RS, 90610-000 · CNES 2232928

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital de Clínicas de Porto Alegre (HCPA)

Rua Ramiro Barcelos, 2350 Bloco A - Av. Protásio Alves, 211 - Bloco B e C - Santa Cecília, Porto Alegre - RS, 90035-903 · CNES 2237601

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário da UFSC (HU-UFSC)

R. Profa. Maria Flora Pausewang - Trindade, Florianópolis - SC, 88036-800 · CNES 2560356

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital das Clínicas da FMUSP

R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas da UNICAMP

R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas de Ribeirão Preto (HCRP-USP)

R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto - SP, 14015-010 · CNES 2082187

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Instituto da Criança e do Adolescente (ICr-HCFMUSP)

Av. Dr. Enéas Carvalho de Aguiar, 647 - Cerqueira César, São Paulo - SP, 05403-000 · CNES 2081695

Serviço de Referência

Rota
Erros Inatos do Metabolismo

UNIFESP / Hospital São Paulo

R. Napoleão de Barros, 715 - Vila Clementino, São Paulo - SP, 04024-002 · CNES 2688689

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo
Sobre os centros SUS: Estes centros são habilitados pelo Ministério da Saúde como Serviços de Referência em Doenças Raras ou Serviços de Atenção Especializada. O atendimento é pelo SUS, com encaminhamento da rede de atenção básica.

Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.

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Ensaios clínicos abertos e novidades científicas recentes

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Publicações mais relevantes

Timeline de publicações
0 papers (10 anos)
#1

Tyrosine Hydroxylase Deficiency Impairs TH Axonal Transport, Brain Function, and Neuronal Plasticity.

Journal of inherited metabolic disease2026 Mar

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder caused by biallelic pathogenic variants in the Th gene, leading to a deficiency in the rate-limiting enzyme for the synthesis of dopamine (DA) and other catecholamine neurotransmitters. THD is associated with dystonia and infantile parkinsonism with a broad and complex spectrum and variable response to l-Dopa therapy. TH1-p.R202H is a frequent THD variant that affects TH stability and activity. The Th knock-in (Th-ki) mice with the equivalent mutation (Th-p.R203H) present reduced TH and DA levels, biological and molecular alterations, different phosphorylation patterns and altered distribution of dopaminergic markers relative to wild-type mice. Th-ki mice displayed significantly reduced TH, especially in the striatum, but also in the cortex, olfactory bulb, cerebellum, substantia nigra, globus pallidus, and spinal cord, a decrease that is not associated with dopaminergic neuronal degeneration. No changes were observed in Th-mRNA expression, and the decreased level of TH in the concrete brain areas in Th-ki mice appears to be due to defective TH protein axonal transport. Moreover, we characterized the development of dopaminergic neurons in the substantia nigra and neuronal plasticity in various brain regions. Our results indicated that alterations in TH expression within specific striatal GABAergic interneurons due to TH deficiency may potentially disrupt the balance of inhibitory neurotransmission in the striatum. Overall, our findings demonstrate that TH deficiency disrupts striatal inhibitory circuitry and triggers compensatory neuronal plasticity, without causing neuronal degeneration.

#2

Synchronous activation of striatal cholinergic interneurons induces local serotonin release.

Nature communications2026 Mar 16

Striatal cholinergic interneurons (CINs) can drive local dopamine release via nicotinic acetylcholine receptors (nAChRs) expressed on dopaminergic axons, but their role in modulating serotonin (5-HT) signaling is poorly understood. Here, we show that synchronous activation of CINs directly triggers local 5-HT release in the dorsal striatum via nAChRs expressed on serotonergic axons. This CIN-5-HT coupling is not detectable in the ventral striatum, despite its substantially denser serotonergic innervation. The nAChR-dependent release not only increases 5-HT levels in the dorsal striatum, but also expands the spatial footprint of serotonergic signaling. In Sapap3-/- mice, a model of obsessive-compulsive disorder (OCD)-like behavior, this mechanism is exaggerated due to a hypercholinergic state, selectively amplifying the nAChR-dependent component of monoamine release. These findings demonstrate a regionally confined form of acetylcholine-5-HT crosstalk in the striatum and identify CINs as regulators of 5-HT dynamics in both healthy and pathological states.

#3

Pregnanolone Glutamate: A Dual-Fate Delivery System for Neuroactive Steroids in Perinatal Focal Cerebral Ischemia.

International journal of molecular sciences2026 Mar 09

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood-brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG-; multi-tissue subset: n = 6 PG+, n = 21 PG-). Our data revealed a "dual-fate" mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a "metabolic sink", passively accumulating metabolites generated in peripheral organs-such as 17-hydroxypregnanolone-despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced "metabolic segregation" within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile-combining metabolic segregation with active central buffering-defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites-several with previously established GABAergic and neuroprotective activity-without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model.

#4

Deletion of TRPA1 Ion Channel Modulates the Central Stress Responses in a Mouse Model of Posttraumatic Stress Disorder.

Cells2026 Feb 28

Background: Posttraumatic stress disorder (PTSD) is a mental illness in which central stress-regulating regions, including locus coeruleus (LC) and paraventricular nucleus of hypothalamus (PVN), play key roles. Clonidine, a central sympatholytic drug, can inhibit LC activity and reduce PTSD-related symptoms, suggesting noradrenergic involvement. Glia-driven immune mechanisms may link LC activity to PVN responses. Since TRPA1 ion channel is implicated in both neuroinflammation and stress adaptation, we aimed to determine whether its presence modulates the function of brain structures contributing to PTSD-related alteration in central stress adaptation. Methods: Foot shock PTSD model was applied to Trpa1 wild-type (WT) and knockout (KO) mice, and outcomes were assessed four weeks later. Immunohistochemistry was used to evaluate tyrosine hydroxylase (TH) levels in the LC and glial activation in the PVN. Behavioral effects of clonidine and circulating corticosterone levels were also examined. Results: Stress increased LC/TH immunoreactivity and PVN glial activation. Trpa1 deletion exaggerated LC/TH responses but reduced PVN astrocyte activation. Clonidine increased freezing and decreased jumping (a hyperarousal marker). KO mice showed enhanced jumping and did not respond to clonidine. Corticosterone levels remained unchanged. Conclusions: TRPA1 may support stress adaptation in PTSD by regulating LC noradrenergic output and PVN neuroinflammation, independently of α2-adrenergic signaling.

#5

Treatment gaps in guideline-directed medical therapy for HFrEF in Singapore: findings from a multicentre retrospective cohort study.

BMJ open2026 Mar 12

To describe prescription patterns, dosing and persistence of guideline-directed medical therapy (GDMT) among patients with heart failure with reduced ejection fraction in Singapore, and to identify factors associated with the use of quadruple therapy (ACE inhibitor (ACEi)/angiotensin II receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), β-blocker, mineralocorticoid receptor antagonist (MRA) and sodium-glucose cotransporter-2 (SGLT2) inhibitor). Retrospective, observational cohort study. Secondary and tertiary care settings across seven public hospitals in Singapore. 3999 adults hospitalised from 2020 to 2022 with a first heart failure-related admission and left ventricular ejection fraction ≤40%. Patients with absolute contraindications to specific GDMT classes were excluded from eligibility calculations. Primary outcomes were the proportions of eligible patients prescribed each GDMT class and quadruple therapy at discharge. Secondary outcomes were 6-month prescription patterns, dose attainment and predictors of quadruple therapy use. Among eligible patients, 80%-99% met criteria for each GDMT drug class, yet only 29% received quadruple therapy at discharge in 2022. Prescription rates for ACEi/ARB/ARNI (67%), beta-blockers (89%), MRAs (40%), and SGLT2 inhibitors (46%) remained suboptimal despite high eligibility. At discharge, over 90% of patients on ACEi/ARB/ARNI and beta-blockers received ≤50% of target doses. By 6 months, prescription rates declined by 16% for ACEi/ARB/ARNI, 26% for beta-blockers and 7% for MRAs, while SGLT2 inhibitor use increased. Older age (OR 0.97, 95% CI 0.96 to 0.98) and chronic kidney disease stage 3a-4 (OR 0.65 to 0.04) were associated with lower odds of receiving quadruple therapy, while significant institutional variation was observed. Despite high eligibility, uptake and optimisation of GDMT remain poor in Singapore, with substantial treatment gaps driven by underprescription, inadequate dosing and discontinuation. Interventions targeting clinician awareness, postdischarge support and institutional practice variation may improve adherence to guideline-recommended therapy.

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Valproic Acid-Induced Autistic-Like Behavior Is Accompanied by Intestinal Damage Driving Changes in Gut Permeability in a Sex-Dependent Way in Rats.

Journal of neurochemistry
2025

Structural basis for pharmacotherapeutic action of triple reuptake inhibitors.

Nature communications
2026

Time-specific perturbation of the serotonergic system differentially modulates the transcriptional landscape of hippocampal subregions in female rats.

Biochemical pharmacology
2026

Evaluating the adenosine hypothesis of restless legs syndrome and its implications for current and future treatment strategies.

Expert review of neurotherapeutics
2026

A co-culture model of dopaminergic and glutamatergic neurons derived from patients with idiopathic schizophrenia reveals a hypodopaminergic phenotype.

Molecular psychiatry
2025

Optogenetic regulation of chloride ions in reactive astrocytes may mitigate Parkinson's disease pathology.

Scientific reports
2025

Investigating the Potential Roles of Environmental Exposures on the Pathology of Amyotrophic Lateral Sclerosis by Overlap Analysis.

Neurotoxicity research
2025

[Potential biological mechanisms underlying spaceflight-induced depression symptoms in astronauts].

Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences
2025

Sodium butyrate-induced autophagy in colorectal cancer unveils the Ca²⁺/CaMKKβ signaling pathway as a potential therapeutic target.

Scientific reports
2026

Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.

Experimental neurology
2025

The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration.

International journal of molecular sciences
2025

Characterization of the functional and clinical impacts of CACNA1A missense variants found in neurodevelopmental disorders.

Science translational medicine

Associações

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Comunidades

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Doenças relacionadas

Doenças com sintomas parecidos — ajudam quem ainda está buscando diagnóstico

Ordenadas pelo número de sintomas em comum.

Referências e fontes

Bases de dados externas citadas neste artigo

Publicações científicas

Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.

  1. Tyrosine Hydroxylase Deficiency Impairs TH Axonal Transport, Brain Function, and Neuronal Plasticity.
    Journal of inherited metabolic disease· 2026· PMID 41872043mais citado
  2. Synchronous activation of striatal cholinergic interneurons induces local serotonin release.
    Nature communications· 2026· PMID 41839847mais citado
  3. Pregnanolone Glutamate: A Dual-Fate Delivery System for Neuroactive Steroids in Perinatal Focal Cerebral Ischemia.
    International journal of molecular sciences· 2026· PMID 41828722mais citado
  4. Deletion of TRPA1 Ion Channel Modulates the Central Stress Responses in a Mouse Model of Posttraumatic Stress Disorder.
    Cells· 2026· PMID 41827861mais citado
  5. Treatment gaps in guideline-directed medical therapy for HFrEF in Singapore: findings from a multicentre retrospective cohort study.
    BMJ open· 2026· PMID 41819588mais citado
  6. Advances in calcium signalling research for the diagnosis and treatment of depression.
    Ann Med· 2026· PMID 41787814recente
  7. N(6)-adenosine methylation enhances nuclear mRNA export through METTL3 and NUP93.
    Nat Cell Biol· 2026· PMID 41786887recente
  8. Chronic Histamine Exposure Promotes Melanogenesis via ORAI1-STIM1-Mediated Calcium Signaling Remodeling.
    Int J Mol Sci· 2026· PMID 41752190recente
  9. Characterization of cardiac disease-associated mutations in RyR2 Ca(2+)- and caffeine-binding sites.
    Am J Physiol Cell Physiol· 2026· PMID 41740622recente
  10. Placental iron transport under maternal stress: a missing link in foetal programming and mental health.
    EBioMedicine· 2026· PMID 41690249recente

Bases de dados e fontes oficiais

Identificadores e referências canônicas usadas para montar este verbete.

  1. ORPHA:79169(Orphanet)
  2. MONDO:0019219(MONDO)
  3. GARD:18950(GARD (NIH))
  4. Variantes catalogadas(ClinVar)
  5. Busca completa no PubMed(PubMed)
  6. Q55788541(Wikidata)

Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.

Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar

Doença do metabolismo das aminas biogênicas
Compêndio · Raras BR

Doença do metabolismo das aminas biogênicas

ORPHA:79169 · MONDO:0019219
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