MUC1-related autosomal dominant tubulointerstitial kidney disease (ORPHA:88949)
A rare autosomal dominant tubulointerstitial kidney (ADTKD) disease due to MUC1 mutations characterized clinically by a bland urinalysis (absence of blood or protein in the urine), and chronic kidney disease leading to end-stage kidney disease (ESKD) between 20 and 80 years.
Epidemiology
Whilst prevalence data is limited, prevalence is estimated at 1/1,400,000 in the USA and 1/250,000 in Ireland. The disease has equal prevalence among all studied racial groups and genders.
Clinical description
Chronic kidney disease usually is first evident in the early twenties. Patients will have slowly progressive loss of kidney function, between 1 and 3 ml/min/1.73m2/year. The mean age of ESKD is approximately 45 years of age, although this varies widely from 20 to over 70 years of age, even among family members with the same mutation. The reason for this variation in age of ESKD is unclear.
Etiology
ADTKD-MUC1 is caused by frameshift mutations in the MUC1 gene, all of which result in the creation of the same frameshift protein. The most common mutation (responsible for approximately 95% of cases) is a cytosine duplication within a tract of seven cytosines. The protein deposits in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) where it leads to cellular stress, early cell death, and progressive kidney failure.
Diagnostic methods
Diagnosis should be considered in families where a parent and child have chronic kidney disease, and urinalysis reveals no blood and little or no protein. De novo mutations may arise and are difficult to identify. Patients should first undergo multi-gene panel testing or whole exome sequencing for other mutations that cause ADTKD and then undergo specialized genetic testing for the MUC1 cytosine duplication, which is causative in 95% of cases of ADTKD-MUC1. This specific test is available in certain laboratories in Europe (see Orphanet Diagnostic Tests) and the USA. Multigene panels, whole exome, and whole genome sequencing do not detect this duplication. If negative, other causative mutations can be identified immunohistochemically in a research setting.
Differential diagnosis
ADTKD-UMOD is clinically very similar, distinguished only by the higher prevalence of gout. Most other conditions have other associated symptoms, but when these symptoms are less severe or not clinically noted, ADTKD-MUC1 should be considered. These include kidney disease related to DNAJB11, IFT140, or HNF1B, and, in rare cases, Alagille syndrome.
Antenatal diagnosis
Due to the difficulty in genetic testing for MUC1 variants, antenatal diagnosis is not currently available in the USA but is available in Europe.
Genetic counseling
The disorder is autosomal dominant. Counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Genetic testing in childhood is not advised as patients are asymptomatic and may not have symptoms of CKD for more than two decades. Relatives should be informed of their risk of ADTKD-MUC1, as the disease is often misdiagnosed, and reaching out to family members can prevent the need for kidney biopsy or inappropriate treatment.
Management and treatment
There are currently no specific therapies available. Sodium glucose-2 transport inhibitors (SGLT2 inhibitors) are indicated in chronic kidney disease and may be helpful in ADTKD. Patients with ADTKD-MUC1 are excellent transplant candidates, as the disease does not recur in the transplanted kidney and most patients do not have other comorbid conditions. The goal should be transplant without ever needing dialysis. Family members should be screened for the familial MUC1 mutation to see if they can donate. Major advances are occurring in kidney disease management, with placement of pig kidneys, CRISPR technology to treat genetic disorders, and advances in immunosuppression-free kidney transplantation.
Prognosis
Patients usually develop end-stage kidney disease at a mean age of 45 years, but there is wide inter- and intra-familial variation. Some family members may go on dialysis in their twenties, while other family members may not start dialysis until past 70 years of age. Survival post-transplant is comparable to the general ESKD transplant population.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Pr Anthony BLEYER  - Pr Stanislav KMOCH