Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis

Poswar, Fabiano de Oliveira; Fonseca, Raymundo Mesko Tomkowski da; Albuquerque, Leonardo Cordenonzi Pedroso de; Zhou, Qing; Jardim, Laura Bannach; Monte, Thaís Lampert; Aksentijevich, Ivona; Saute, Jonas Alex Morales

doi:10.1007/s00415-016-8070-y

Cited by 23 publications

(13 citation statements)

References 8 publications

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“…In all families but family J, DNA from relatives was available and the variants could be confirmed to be located in trans. Eight patients were compound heterozygous and five were homozygous for mutations c. (Thr360Ala) and deletion of exon 7 [7,[15][16][17][18]. Seven novel mutations were found in families B, E, G, H and K ( Fig.…”

Section: Demographic Datamentioning

confidence: 98%

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience

et al. 2018

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Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.

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Section: Demographic Datamentioning

confidence: 98%

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience

et al. 2018

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“…1 In the severe spectrum of the disease are patients presenting with cranial nerve palsy, diplegia, paraplegia, peripheral polyneuropathy due to perineuritis, ataxia, sensorineural hearing loss, mononeuritis multiplex, labyrinthitis, neuromyelitis, encephalopathy and cerebral atrophy. 1,2,73,74,76,79,81,82 At the histology level, the brain lesions correspond to erythrocyte extravasation in brain parenchyma.…”

Section: Vasculitismentioning

confidence: 99%

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small‐ and medium‐size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro‐inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti‐TNF therapy with etanercept and that is the first‐line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients’ refractory to anti‐cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine‐tune and steer future therapeutic strategies.

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“…Ophthalmologic complications including vision loss, central retinal artery occlusion, optic nerve atrophy, uveitis, diplopia, nystagmus, and strabismus have all been described ( 9 , 40 ). Peripheral neuropathy is noted in half of patients in some cohorts and spastic paraplegia has been reported as a presenting symptom of DADA2 ( 36 , 43 ).…”

Section: Dada2 As a Monogenic Cause Of Vasculopathymentioning

confidence: 99%

Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2

Lee

2018

Front. Pediatr.

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Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of systemic vasculopathy that often presents during early childhood. Linked to biallelic mutations in ADA2 (previously CECR1), DADA2 was initially described as a syndrome of recurrent fever, livedo racemosa, early-onset strokes, and peripheral vasculopathy that resembles polyarteritis nodosum. However, the wide spectrum of clinical findings and heterogeneity of disease, even among family members with identical mutations, is increasingly recognized. Evidence of systemic inflammation and vasculopathy is not uniformly present in DADA2 patients and some can remain asymptomatic through adulthood. Humoral immunodeficiency characterized by low immunoglobulin levels and increased risk of infection is another common feature of DADA2. Variable cytopenias including pure red cell aplasia that mimics Diamond-Blackfan anemia can also be primary manifestations of DADA2. How defects in a single gene translate into these heterogeneous presentations remains to be answered. In this review, we will summarize lessons learned from the pleiotropic clinical manifestations of DADA2.

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Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis

Cited by 23 publications

References 8 publications

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2

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