A number sign (#) is used with this entry because of evidence that Kaya-Barakat-Masson syndrome (KABAMAS) is caused by homozygous or compound heterozygous mutation in the YIF1B gene (619109) on chromosome 19q13.

Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development with variable motor abnormalities, such as axial hypotonia, peripheral spasticity, dystonia, and poor coordination, resulting in the inability to sit or walk. Affected individuals have impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Dysmorphic features are generally not present. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood (summary by AlMuhaizea et al., 2020 and Diaz et al., 2020).

AlMuhaizea et al. (2020) reported 6 children from 5 unrelated families, 4 of which were consanguineous, with a similar neurodevelopmental disorder. The patients, who ranged in age from 4 to 11 years, had severely impaired psychomotor development with axial hypotonia and inability to sit, walk, or, in some cases, roll over, lack of head control, poor fine motor skills, absent language, and irritability. Most had poor eye contact and only achieved social smiling. Other motor abnormalities included limb dystonia, spasticity, choreiform movements, and dyskinesia. The patients had feeding difficulties and dysphagia, necessitating tube-feeding in 2 patients, and poor overall growth with short stature and microcephaly. Two patients developed seizures at 6 to 8 months of age that could be controlled; 1 patient had cortical blindness. Three patients had nonspecific brain imaging findings, including hypomyelination, thin corpus callosum, and cerebral and cerebellar atrophy. Dysmorphic features were not noted, although 2 patients had hip dislocation/dysplasia and 1 patient had foot deformities.

Diaz et al. (2020) reported 10 patients from 6 unrelated families with a similar neurodevelopmental disorder associated with YIF1B mutations identified through the GeneMatcher program. Four patients in 2 families (families 1 and 2) died between 7 and 15 months of age. Four living patients from 3 families (families 3, 5, and 6) were between 4 and 11 years of age, and 2 sibs (family 4) were 25 and 35 years of age. The families originated from France, Saudi Arabia, Iran, Canada, and Italy; several were consanguineous. The patients presented in infancy with severely impaired psychomotor development. None of the patients, except the adult sibs from family 4, achieved sitting, walking, or head control. All had profoundly impaired intellectual development with absent speech and poor eye contact. Most had feeding difficulties and axial hypotonia, and some had peripheral hypertonia or spasticity with hyperreflexia; a few patients had choreoathetosis or dystonia. Three patients had central hypoventilation: 1 died and the other 2 required ventilatory assistance. More than half of patients had variable ocular abnormalities, including strabismus, optic atrophy, nystagmus, and abnormal visual evoked potentials, suggesting retinal dysfunction. Almost all developed infantile spasms or myoclonic seizures in the first months of life, which were often refractory to treatment. The 2 sibs from family 4, who carried a missense mutation (see MOLECULAR GENETICS), had a slightly less severe phenotype. They began walking at 4 to 5 years of age with a spastic gait and started speaking with a few words at 7 to 8 years. They had severely impaired intellectual development with IQ ranging from 45 to 48. These sibs had onset of tonic-clonic seizures at 20 and 7 years, respectively. Other features observed in the cohort included talipes varus and scoliosis. Brain imaging in some patients showed cerebral, cerebellar, or pontine atrophy, or nonspecific white matter abnormalities, although many patients had normal brain imaging.

Medico Salsench et al. (2021) described 8 new patients with KABAMAS due to biallelic pathogenic variants in the YIF1B gene and reviewed the literature on previously reported cases. The disorder was characterized by severe to profound neurodevelopmental delay, cognitive impairment, neurologic sequelae, seizures, and microcephaly. All patients presented early in life with a progressive encephalopathy with global developmental delay and cognitive impairment. Almost all had feeding problems, axial hypotonia, and limb spasticity, with seizures in 14 of 22 (64%) patients from whom information was available. Microcephaly was seen in 15 of 23 (65%) patients. About half of the patients showed signs of dystonia, dyskinesia, or microcephaly. Hypoventilation was seen in 5 of 18 (23%) patients and appeared to be associated with brainstem atrophy. Brain imaging abnormalities were seen in about two-thirds of patients. The ability to meet limited developmental milestones (e.g., head control, independent sitting, limited speech) was seen only in patients with missense mutations, suggesting that residual YIF1B activity is present in these patients, consistent with in vitro data.

The transmission pattern of KABAMAS in the families reported by AlMuhaizea et al. (2020) was consistent with autosomal recessive inheritance.

In 6 patients from 5 unrelated families with KABAMAS, AlMuhaizea et al. (2020) identified homozygous loss-of-function mutations in the YIF1B gene (619109.0001-609109.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families that could be studied. None were present in the gnomAD database. Functional studies of the variants were not performed, but all were predicted to result in a complete loss of protein function.

In 10 patients from 6 unrelated families with KABAMAS, Diaz et al. (2020) identified homozygous or compound heterozygous mutations in the YIF1B gene (see, e.g., 619109.0001, 619109.0003-619109.0006). The patients, who originated from various countries, including France, Saudi Arabia, Iran, Canada, and Italy, were ascertained through the GeneMatcher database after whole-exome sequencing identified biallelic YIF1B mutations. All but one mutation were nonsense, splice site, or frameshift; the exception was a missense variant (K123Q; 609109.0005) found in 2 sibs from family 4 who had a slightly less severe phenotype. Western blot analysis of some of the mutations showed decreased protein levels, and most were predicted to lack all or most of the transmembrane domains, consistent with a putative loss of function. Patient-derived fibroblasts showed reduced and shortened cilia compared to controls, suggesting ciliary anchoring defects (see ANIMAL MODEL). These findings, together with mouse studies, implicated several cellular processes that were disrupted by the YIF1B mutation, collectively resulting in a neurodevelopmental disorder.

Medico Salsench et al. (2021) described 8 new patients with KABAMAS due to biallelic pathogenic variants in the YIF1B gene and reviewed the literature on previously reported cases. Among the total of 24 cases from 19 families, 18 (75%) mutations were truncating or whole gene deletion and 6 (25%) were missense variants. All YIF1B missense variants were located in or close to the transmembrane domains and were absent from gnomAD, except for 1 that was found once in heterozygous state. All changed highly conserved residues. Based on introduction of missense variants into an YIF1B expression plasmid, missense variants did not result in significantly reduced YIF1B protein levels.

Diaz et al. (2020) found that knockdown of the Yif1b gene in mice did not cause ventilatory defects or increased susceptibility to seizures, although mutant mice showed impaired visual perception associated with retinal dysfunction and optic atrophy. Basal locomotion was normal, but there were some deficits in fine motor skills and coordination. Mutant mice had delayed cerebral myelination, enlarged ventricles, and cerebellar atrophy associated with a reduction in the number of Purkinje cells due to neurodegeneration and necrosis rather than apoptosis. There were disorganized dendritic trees and the presence of microglia cells. Electron microscopic studies of Purkinje cells showed abnormal fragmentation of the Golgi apparatus, large autophagosome-like vacuoles, and aberrant configuration of the endoplasmic reticulum (ER) with dilated cisterns compared to controls. Male Yif1b-null mice were infertile due to abnormal spermatozoa flagella, which showed microtubule disorganization. Ciliary abnormalities were also observed in cerebellar Purkinje cells, hippocampal pyramidal cells, and fibroblasts. These findings, together with the human results, suggested that YIF1B is essential not only for Golgi and ER morphology and function, but also for primary ciliary integrity. Loss of YIG1B function leads to altered myelination, neuronal death, and Golgi, ER, and ciliary defects with pathology related to disrupted trafficking of proteins, ultimately resulting in neurodevelopmental abnormalities.