Table 1 Phenotypes of the patients.
From: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
P1, female | P2, female | P3, male | P4, female | P5, female | P6, male | |
---|---|---|---|---|---|---|
Ethnicity, country of residence | White, Germany | White, Austria | White, Germany | White, USA | White, Australia | White, USA |
CLPB (NM_030813.4) de novo | c.1211A>C; [=], p.Lys404Thr; [=] | c.[1280C>T]; [=], p.[Pro427Leu]; [=] | c.[1678G>A];[=], p[Gly560Arg];[=] | c.[1678G>A];[=], p[Gly560Arg];[=] | c.[1681C>T];[=], p[Arg561Trp];[=] | c.[1681C>T];[=], p[Arg561Trp];[=] |
Current age (years) | 3.0 | 19 months (deceased) | 7.0 | 7.8 | 12.4 | 5.3 |
Presenting age: signs & symptoms | Neonatal: AMC, 18 months: seizures | Neonatal: seizures, virtually no development | Neonatal: oral and perianal abscesses, 15 months neutropenia | Neonatal: sepsis, neutropenia | 12 months: recurrent infections, neutropenia, DD | Neonatal: umbilical cord stump infection |
Lowest ANC value (1.5–8.5 × 109/ml) | Normal range | 0.6–0.9 (during infections) | 0.7–1.2 | 0.0–0.1 | 0.4 | 0.1 |
Neutropenia | No | Moderate during infections | Moderate, controlled with GCSF | Severe, HSCT 15 months | Severe, not controlled with GCSF | Severe, HSCT 5 years |
Other hematological issues | No | No | Mild anemia | Intermittent mild anemia | Mild anemia | Normochromic anemia, mild anisopoikilocytosis |
Best motor achievement | Walking independently, running with assistance | Virtually no development | Sitting with assistance, nonambulatory | Ambulatory with a wide based gait not able to run, able to jump with both feet off the ground | Currently: can sit upright in a wheel chair | Milestones on time, able to run, jump, go up/down stairs, well coordinated |
Best language achievement | Speaks 50 words, starts 2 word sentences, uses gestures | Virtually no development | Nonverbal | Verbal communication with 1–2 word sentences not able to converse still makes progress | 10–20 words, receptive > expressive language, uses communication device | Full comprehension, speaks in full sentences, articulation deficits, mild speech delay |
Loss of skills, age at loss | No | Virtually no development | Yes, lost standing and walking skills; some steps with help at age 3 years, no further development since | Yes, after BMT e.g., loss of “animal sounds” | Yes, lost ability to use walking frame at 9.5 years | No |
Muscle tone | Generalized hypotonia, no spasticity | Truncal and oral hypotonia with limb spasticity | Truncal hypotonia with limb spasticity | Mild truncal hypotonia with limb spasticity | Truncal hypotonia with limb spasticity | Normal |
Severity of DD/ID | Moderate | Severe | Severe | Moderate | Moderate | Mild |
Seizures, type | Myoclonic, tonic–clonic, atypical absences, not controlled | Generalized, apnea/bradycardia, hyperextension of the trunk, not controlled | Absences, sometimes with myoclonic aspects, controlled | Atypical absence seizures, controlled | Atypical absence-like episode, not completely controlled | No |
MRI alterations | 12 months: periventricular white matter alterations | Neonatal: normal; 17 months: mild cerebellar atrophy, slight T2-hyperintensities in the central white matter | 3 years: mild global atrophy, diffusely abnormal white matter signal | 5 years: mild cerebellar atrophy; periatrial and periventricular FLAIR signal abnormality with associated volume loss | 15 months: diffusely elevated white matter signal, including cerebellar white matter, indicating delayed myelination 7 years: additionally supratentorial atrophy and abnormal basal ganglia signal (T2) | 5 years: hazy, biparietal periventricular and deep white matter signal; focal thinning of posterior body of corpus callosum |
Microcephaly, secondary | – | + | + | + | + | – |
urinary 3-MGA | + (mild) | + (mild) | + (high) | + (moderate) | + (mild) | + (high) |