Developmental Phenotype of the Rare Case of DJ Caused by a Unique ADNP Gene De Novo Mutation

Levine, Joseph; Cohen, David; Herman, C.; Verloès, Alain; Guinchat, Vincent; Diaz, Lautaro; Cravero, Cora; Mandel, Anne; Gozes, Illana

doi:10.1007/s12031-019-01333-9

Cited by 21 publications

(22 citation statements)

References 49 publications

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“…In the first few years of life, a child may go through multiple surgeries, including open heart surgery with ADNP involved in heart development (13) and affecting congenital heart diseases (5,30). The cognitive impairments (ID) may be very severe; a 7-year-old may behave like a 16-monthold, and the language of a 3-year-old may be equivalent to a 12-month-old, as words are unrecognizable (5,10,31).…”

Section: Rationale For Drug Developmentmentioning

confidence: 99%

The ADNP Syndrome and CP201 (NAP) Potential and Hope

Gozes

2020

Front. Neurol.

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Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Original data showed that Adnp+/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome.

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Section: Rationale For Drug Developmentmentioning

confidence: 99%

The ADNP Syndrome and CP201 (NAP) Potential and Hope

Gozes

2020

Front. Neurol.

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“…De novo mutations in ADNP result in the ADNP syndrome, with children suffering from severe global developmental delays that affect the central and peripheral nervous systems [ 5 ]. Several structural abnormalities in the ADNP syndrome brain were observed including cerebral atrophy, delayed myelination, white matter lesions, and wide ventricles [ 5 , 6 ]. Other pathological outcomes include impairments in motor function, delayed speech acquisition, intestinal and urinary problems [ 5 , 7 ] as well as early tooth eruption [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Kapitansky

Karmon

Sragovich

et al. 2020

Cells

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Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

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“…It is located in the Department of Child and Adolescent Psychiatry of the Pitié-Salpêtrière university hospital. The USIDATU seeks to provide both containment and supportive frameworks for patients [ 10 , 11 ]. The unit is composed of 14 single inpatient rooms and is divided into two sectors: the first for children and adolescents and the second for adults.…”

Section: Methodsmentioning

confidence: 99%

Autism and COVID-19: A Case Series in a Neurodevelopmental Unit

Nollace

Cravero

Abbou

et al. 2020

JCM

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Background: COVID-19 has become pandemic and can impact individuals with autism as well. Here, we report a case series admitted to a neurobehavioral unit dedicated to challenging behaviors in patients with autism. Methods: We describe 16 patients (mean age 20.8 years; range 12–43 years; 76% male) with autism hospitalized between March 2020 and mid-April 2020 for challenging behaviors, for which COVID-19 disease has been suspected and who needed both psychiatric and medical care. A close cooperation with the Infectious and Tropical Diseases Department was organized to limit viral spread and training sessions (e.g., hygiene, clinical COVID-19 monitoring, virus testing) were given to staff members. Results: Most patients had severe autism and severe/moderate intellectual disability. Eleven patients were already in the unit when it was hit by the pandemic, and five were admitted from the community. Based on a virus search via reverse transcriptase polymerase chain reaction (RT-PCR) or serology at the 2-month follow-up, we had 11 confirmed COVID-19 cases. The main COVID-19 symptoms included benign upper respiratory infection signs (N = 9, 81.8%), diarrhea (N = 7, 63.6%), fatigue (N = 7, 63.6%), and respiratory signs (N = 5, 45.5%), including one patient who needed oxygen therapy. Three patients remained asymptomatic and COVID-19-free (including two under immunosuppressive treatments). Among the symptomatic patients, five showed atypical behaviors that we understood as idiosyncratic manifestations (e.g., irrepressible licking behavior). On day 14, only one patient with respiratory dysfunction still had a positive RT-PCR SARS-CoV-2 test. Conclusions: Organizing a COVID+ unit for patients with autism is realistic and requires close collaboration with infectologists. We believe that this initiative should be promoted to limit both the spread of the virus and the ostracism of patients with autism and challenging behaviors.

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Developmental Phenotype of the Rare Case of DJ Caused by a Unique ADNP Gene De Novo Mutation

Cited by 21 publications

References 49 publications

The ADNP Syndrome and CP201 (NAP) Potential and Hope

The ADNP Syndrome and CP201 (NAP) Potential and Hope

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Autism and COVID-19: A Case Series in a Neurodevelopmental Unit

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